Piperazinylacylpiperidine derivatives, their preparation and therapeutic use thereof

ABSTRACT

The invention relates to substituted 1-piperazinylacylpiperidine derivatives of general formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             in which: 
             n is 1 or 2; 
             p is 1 or 2; 
             R 1  represents a halogen atom; a trifluoromethyl radical; a (C 1 -C 4 )alkyl; a (C 1 -C 4 )alkoxy; a trifluoromethoxy radical; 
             R 2  represents a hydrogen atom or a halogen atom; 
             R 3  represents a hydrogen atom; a group —OR 5 ; a group —CH 2 OR 5 ; a group —NR 6 R 7 ; a group —NR 8 COR 9 ; a group —NR 8 CONR 10 R 11 ; a group —CH 2 NR 12 R 13 ; a group —CH 2 NR 8 CONR 14 R 15 ; a (C 1 -C 4 )alkoxycarbonyl; a group —CONR 16 R 17 ; 
             or else R 3  constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; 
             R 4  represents an aromatic group selected from: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             the said aromatic groups being unsubstituted or being mono- or disubstituted by a substituent selected independently from a halogen atom; a (C 1 -C 4 )alkyl; a (C 1 -C 4 )alkoxy; a trifluoromethyl radical; 
             Preparation process and therapeutic application.

The present invention relates to substituted 1-piperazinylacylpiperidinederivatives, their preparation and their therapeutic application.

The compounds according to the present invention exhibit affinity forthe neurotrophin receptor p75^(NTR).

Neurotrophins belong to a family of proteins which possess a similarstructure and similar functions and include nerve growth factor (NGF),BDNF (Brain Derived Neurotrophic Factor), neurotrophin-3 (NT-3),neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). The biologicaleffects of these proteins (survival and differentiation) are exertedthrough interaction with membrane receptors having tyrosine kinaseactivity (trk-A, trk-B and trk-C) (H. THOENEN, Science, 1995, 270,593-598; G. R. LEWIN and Y. A. BARDE, Annu. Rev. Neurosci., 1996, 19,289-317; M. V. CHAO, J., Neurobiol., 1994, 25, 1373-1385; M. BOTHWELL,Annu. Rev. Neurosci., 1995, 18, 223-253; G. DECHANT and Y. A. BARDE,Curr. Opin. Neurobiol., 1997, 7, 413-418). However, many studies showthe preponderant role of the p75^(NTR) receptor in the activity ofneurotrophins.

The p75^(NTR) receptor, the receptor for all neurotrophins, is atransmembrane glycoprotein of the tumour necrosis factor (TNF) receptorfamily (W. J. FRIEDMAN and L. A. GREENE, Exp. Cell. Res., 1999, 253,131-142; J. MELDOSIS et al., Trends Pharmacol. Sci., 2000, 21, 242-243).A number of biological functions are attributed to the p75^(NTR)receptor: on the one hand, the modulation of the affinity ofneurotrophins for trk receptors; on the other hand, in the absence oftrk, induction of a signal for cell death by apoptosis which occursthrough homodimerization of the receptor and activation of the ceramidepathway.

Apoptosis, or programmed cell death, is a physiological mechanism forelimination of cells in numerous tissues. In particular, apoptosis playsa preponderant role in embryogenesis, morphogenesis and cell renewal.Apoptosis is a genetically controlled phenomenon which only occurs at anadvanced and irreversible stage of cell lesion.

Many studies show that apoptosis occurs in several pathologies of thecentral nervous system such as amyotrophic lateral sclerosis, multiplesclerosis, Alzheimer's, Parkinson's and Huntington's diseases and priondiseases. Furthermore, neuronal death through apoptosis also occurs veryearly after cerebral and cardiac ischaemia. Cell death is also apreponderant phenomenon in atherosclerosis; indeed, the necrosis zonesin primary atherosclerotic lesions in humans are evaluated at 80% (M. L.BOCHATON-PIALAT et al., Am. J. Pathol., 1995, 146, 1-6; H. PERLMAN,Circulation, 1997, 95, 981-987). Apoptosis is also involved inmechanisms leading to cell death following cardiac ischaemia-reperfusion(H. YAOITA et al., Cardiovasc. Res., 2000, 45, 630-641).

Several studies show that the p75^(NTR)-dependent pro-apoptotic signalis observed in various cell types including neuronal cells,oligodendrocytes, Schwann cells and also hepatic, cardiac and smoothmuscle cells (J. M. FRADE et al., Nature, 1996, 383, 166-168; P.LASACCIA-BONNEFIL et al., Nature, 1996, 383, 716-719; M. SOILU-HANNINENet al., J. Neurosci., 1999, 19, 4828-4838; N. TRIM et al., Am. J.Pathol., 2000, 156, 1235-1243; S. Y. WANG et al., Am. J. Pathol., 2000,157, 1247-1258). Moreover, a number of experiments carried out in vivoshow an increase in the expression of p75^(NTR) following ischaemia inregions of the brain and of the heart in which massive apoptosis isrecorded. These results therefore suggest that p75^(NTR) may play apreponderant role in the mechanisms leading to neuronal death throughapoptosis post ischaemia (P. P. ROUX et al., J. Neurosci., 1999, 19,6887-6896; J. A. PARK et al., J. Neurosci., 2000, 20, 9096-9103).

The p₇₅ ^(NTR) receptor is described as a cellular target for the prionpeptide (V. DELLA-BIANCA et al., J. Biol. Chem., 2001, in press) and forthe β-amyloid peptide (S. RABIZADEH et al., Proc. Natl. Acad. Sci. USA,1994, 91, 10703-10706) and would thus be involved in apoptotic phenomenainduced by these compounds. These results support the hypothesisaccording to which p75^(NTR) would play an important role in neuronaldeath induced by the infectious prion protein (transmissible spongiformencephalopathy) or by the beta-amyloid protein (Alzheimer's disease).

Recent studies suggest that the p75^(NTR) receptor might also play animportant role in axonal regeneration, via its function as co-receptorfor the Nogo receptor (WONG et al., Nature Neurosci., 2002, 5,1302-1308; Kerracher and Winton, Neuron, 2002, 36, 345-348). Indeed,several myelin-associated proteins (myelin-associated glycoprotein, MAG,Nogo-A and oligodendrocyte myelin glycoprotein OMgp) inhibit nerveregeneration at the central level during medullary or cranial trauma.These proteins are located in the membrane of the oligodendrocytesdirectly adjacent to the axon and inhibit neuritic growth by bindingwith a high affinity to the Nogo receptor located on the axonalmembrane. The p75^(NTR) receptor is associated with the Nogo receptorand is involved in the signalling of the inhibitory effects of thesemyelin proteins in relation to axonal growth. As a result, the p75^(NTR)receptor plays a major role in the regulation of neuronal plasticity andin neuron-glia interactions and represents a therapeutic target ofchoice for promoting nerve regeneration.

At the peripheral level, recent studies show an increase in theexpression of p75^(NTR) and of neurotrophins and a massive apoptosis inatherosclerotic lesions. Furthermore, a pro-angiogenic and vasodilativeeffect of NGF is also recorded. Finally, a novel form of p75^(NTR) whichis truncated in the extracellular part has been identified as well asits major role in established vasculogenesis (D. VON SHACK et al.,Nature Neuroscience, 2001, 4, 977-978). All these recent data suggestthat p₇₅ ^(NTR) in its whole or truncated form could also play apreponderant role in vascular pathologies.

A number of compounds are known to interact with the trkA/NGF/p75^(NTR)system or to possess an NGF-type activity. Thus, patent application WO00/59893 describes substituted pyrimidine derivatives which demonstratean NGF-type activity and/or which increase the activity of NGF on PC12cells. Patent applications WO 00/69828 and WO 00/69829 describepolycyclic compounds which inhibit the binding of NGF to the p75^(NTR)receptor in cells which do not express the trkA receptor. Application WO94/11373 describes pyridazinoquinazolone derivatives which bind to theneurotrophin receptor p75^(NTR). Application WO 94/22866 describespyrazoloquinazolone derivatives which specifically bind to NGF so as toavoid its attachment to the p75^(NTR) receptor but allowing it tointeract with the trk receptor. Application WO 01/49684 describessubstituted tetrahydropyridine derivatives which possess activityvis-à-vis the modulation of TNF-alpha.

New 1-piperazinylacylpiperidine derivatives have now been found whichexhibit affinity for the receptor p75^(NTR).

The present invention provides compounds of the formula (I):

in which:

-   -   n is 1 or 2;    -   p is 1 or 2;    -   R₁ represents a halogen atom; a trifluoromethyl radical; a        (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethoxy radical;    -   R₂ represents a hydrogen atom or a halogen atom;    -   R₃ represents a hydrogen atom; a group —OR₅; a group —CH₂OR₅; a        group —NR₆R₇; a group —NR₈COR₉; a group —NR₈CONR₁₀R₁₁; a group        —CH₂NR₁₂R₁₃; a group —CH₂NR₈CONR₁₄R₁₅; a (C₁-C₄)alkoxycarbonyl;        a group —CONR₁₆R₁₇;    -   or else R₃ constitutes a double bond between the carbon atom to        which it is attached and the adjacent carbon atom of the        piperidine ring;    -   R₄ represents an aromatic group selected from:

-   -    the said aromatic groups being unsubstituted or being mono- or        disubstituted by a substituent selected independently from a        halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethyl        radical;    -   R₅ represents a hydrogen atom; a (C₁-C₄)alkyl; a        (C₁-C₄)alkylcarbonyl;    -   R₆ and R₇ represent each independently a hydrogen atom or a        (C₁-C₄)alkyl;    -   R₈ represents a hydrogen atom or a (C₁-C₄)alkyl;    -   R₉ represents a (C₁-C₄)alkyl or a group —(CH₂)_(m)—NR₆R₇;    -   m is 1, 2 or 3;    -   R₁₀ and R₁₁ represent each independently a hydrogen atom or a        (C₁-C₄)alkyl;    -   R₁₂ and R₁₃ represent each independently a hydrogen atom or a        (C₁-C₅)alkyl; R₁₃ may also represent a group —(CH₂)_(q)—OH or a        group —(CH₂)_(q)—S—CH₃;    -   or else R₁₂ and R₁₃, together with the nitrogen atom to which        they are attached, constitute a heterocycle selected from        aziridine, azetidine, pyrrolidine, piperidine and morpholine;    -   q is 2 or 3;    -   R₁₄ and R₁₅ represent each independently a hydrogen atom or a        (C₁-C₄)alkyl;    -   R₁₆ and R₁₇ represent each independently a hydrogen atom or a        (C₁-C₄)alkyl; R₁₇ may also represent a group —(CH₂)_(q)—NR₆R₇;    -   or else R₁₆ and R₁₇, together with the nitrogen atom to which        they are attached, constitute a heterocycle selected from        azetidine, pyrrolidine, piperidine, morpholine and piperazine        which is unsubstituted or substituted in position 4 by a        (C₁-C₄)alkyl.

The compounds of formula (I) may exist in the form of bases or additionsalts with acids. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, although the salts of other acids useful for the purification orisolation of compounds of formula (I) also form part of the invention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, specifically in the form of associations or combinations withone or more molecules of water or with a solvent. Such hydrates andsolvates also form part of the invention.

A halogen atom is an atom of bromine, chlorine, fluorine or iodine.

(C₁-C₄)Alkyl or (C₁-C₅)alkyl respectively is a linear or branched alkylradical of one to four carbon atoms or one to five carbon atoms,respectively, such as the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl ortert-pentyl radical.

(C₁-C₄)Alcoxy is a linear or branched alkoxy radical of one to fourcarbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy o tert-butoxy radical.

Among the compounds of formula (I) provided by the invention mention maybe made of the preferred compounds which are defined as follows:

-   -   R₁ is in position 2, 3 or 4 of the phenyl and represents a        trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or        a trifluoromethoxy radical and R₂ represents a hydrogen atom; or        else R₁ is in position 3 of the phenyl and represents a        trifluoromethyl radical and R₂ is in position 4 of the phenyl        and represents a chlorine atom;    -   and/or R₃ represents a hydrogen atom, a hydroxyl, a methoxy, an        (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an        acetylamino, an aminomethyl, a (methylamino)methyl, a        (dimethylamino)methyl, a (diethylamino)methyl, an        (isopropylamino)methyl, an (N-methylisopropylamino)methyl, an        (isobutylamino)methyl; an (N-methylisobutylamino)methyl, an        (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an        aminocarbonyl, an azetidin-1-ylcarbonyl; or else R₃ constitutes        a double bond between the carbon atom to which it is attached        and the adjacent carbon atom of the piperidine ring;    -   and/or R₄ represents a 2-pyridyl, a 6-methyl-2-pyridyl, a        3-(trifluoromethyl)-2-pyridyl, a 5-(trifluoromethyl)-2-pyridyl,        a 3-chloro-5-(trifluoromethyl)-2-pyridyl, a 3-pyridyl, a        4-pyridyl, a 3,5-dichloro-4-pyridyl, a 2-pyrazinyl, a        5-chloro-2-pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyl, a        4-(trifluoromethyl)-2-pyrimidinyl, a 6-chloro-2-pyrimidinyl, a        4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a        3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a        3(2H)-pyridazinone-5-yl or a 3(2H)-pyridazinone-4-yl.

Particular preference is given to the compounds of formula (I) wherein:

-   -   n is 1 or 2;    -   p is 1 or 2;    -   R₁ is in position 2, 3 or 4 of the phenyl and represents a        trifluoromethyl radical, a chlorine atom, a methyl, a methoxy or        a trifluoromethoxy radical and R₂ represents a hydrogen atom; or        else R₁ is in position 3 of the phenyl and represents a        trifluoromethyl radical and R₂ is in position 4 of the phenyl        and represents a chlorine atom;    -   R₃ represents a hydrogen atom, a hydroxyl, a methoxy, an        (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, an        acetylamino, an aminomethyl, a (methylamino)methyl, a        (dimethylamino)methyl, a (diethylamino)methyl, an        (isopropylamino)methyl, an (N-methylisopropylamino)methyl; an        (isobutylamino)methyl; an (N-methylisobutylamino)methyl, an        (isopentylamino)methyl, an (N-methylisopentylamino)methyl, an        aminocarbonyl, an azetidin-1-ylcarbonyl; or else R₃ constitutes        a double bond between the double bond between the carbon atom to        which it is attached and the adjacent carbon atom of the        piperidine ring;    -   R₄ represents a 2-pyridyl, a 6-methyl-2-pyridyl, a        3-(trifluoromethyl)-2-pyridyl, a 5-(trifluoromethyl)-2-pyridyl,        a 3-chloro-5-(trifluoromethyl)-2-pyridyl, a 3-pyridyl, a        4-pyridyl, a 3,5-dichloro-4-pyridyl, a 2-pyrazinyl, a        5-chloro-2-pyrazinyl, a 6-chloro-2-pyrazinyl, a 2-pyrimidinyl, a        4-(trifluoromethyl)-2-pyrimidinyl, a 6-chloro-2-pyrimidinyl, a        4-pyrimidinyl, a 6-chloro-4-pyrimidinyl, a 5-pyrimidinyl, a        3-pyridazinyl, a 6-chloro-3-pyridazinyl, a 4-pyridazinyl, a        3(2H)-pyridazinone-5-yl, a 3(2H)-pyridazinone-4-yl;        in the form of a base or an addition salt with an acid, and also        in the form of a hydrate or solvate.

More preference is given to the compounds of formula (I) wherein

-   -   n is 1;    -   p is 1;    -   R₁ is in position 2, 3 or 4 of the phenyl and represents a        trifluoromethyl radical, a chlorine atom, a methoxy or a        trifluoromethoxy radical and R₂ represents a hydrogen atom; or        else R₁ is in position 3 of the phenyl and represents a        trifluoromethyl radical and R₂ is in position 4 of the phenyl        and represents a chlorine atom;    -   R₃ represents a hydroxyl, a dimethylamino, an aminomethyl, a        (methylamino)methyl, a (dimethylamino)methyl, a        (diethylamino)methyl, an (isopropylamino)methyl, an        (isobutylamino)methyl, an (isopentylamino)methyl, an        (N-methylisopentylamino)methyl or an aminocarbonyl; or else R₃        constitutes a double bond between the carbon atom to which it is        attached and the adjacent carbon atom of the piperidine ring;    -   R₄ represents a 2-pyrazinyl, a 4-pyrimidinyl, a        3(2H)-pyridazinone-5-yl or a 5-(trifluoromethyl)-2-pyridyl;        in the form of a base or an addition salt with an acid, and in        the form of a hydrate or solvate.

Among the compounds of formula (I) provided by the invention particularmention may be made of the following compounds:

-   -   1-[4-(aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   5-[4-[2-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-oxoethyl]-1-piperazinyl]-3(2H)-pyridazinone;    -   1-[4-hydroxy-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   2-[4-(4-pyrimidinyl)-1-piperazinyl]-1-[4-[3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-1-ethanone;    -   2-[4-(2-pyrazinyl)-1-piperazinyl]-1-[4-[2-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-1-ethanone;    -   1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide;    -   1-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(dimethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-(4-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-2-[4-[5-(trifluoromethyl)-2-pyridyl]1-piperazinyl]-1-ethanone;    -   1-[4-[(methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(diethylamino)methyl]4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(isobutylamino)methyl]4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(isopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-[(N-methylisopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;    -   1-[4-hydroxy-4-[3-(trifluoromethoxy)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;        in the form of base or an addition salt of an acid, and in the        form of a hydrate or solvate.

In another of its aspects the present invention provides a process forpreparing compounds of formula (I) in which n=1, characterized in that:

a1) a compound of the formula

in which R₁, R₂ and R₃ are as defined for a compound of formula (I) andHal represents a halogen atom, preferably chlorine or bromine, with theproviso that when R₃ contains a hydroxyl or amine function thesefunctions may be protected, is reacted with a compound of formula

in which p and R₄ are as defined for a compound of formula (I);

b1) and, after deprotection of the hydroxyl or amine functions presentin R₃ where appropriate, the compound of formula (I) is obtained.

Where appropriate, the compound of formula (I) is converted into one ofits addition salts with an acid.

In another of its aspects the present invention provides a process forpreparing compounds of formula (I) in which n=2, characterized in that:

a2) a compound of formula

in which R₁, R₂ and R₃ are as defined for a compound of formula (I),with the proviso that when R₃ contains a hydroxyl or amine functionthese functions may be protected, is reacted with a compound of formula

in which p and R₄ are as defined for a compound of formula (I);

b2) and, after deprotection of the hydroxyl or amine functions presentin R₃ where appropriate, the compound of formula (I) is obtained.

Where appropriate, the compound of formula (I) is converted into one ofits addition salts with an acid.

In step a1) or in step a2), when a compound of formula (IIa) or (IIb) isreacted with a compound of formula (III), the reaction is carried out inthe presence of a base selected from organic bases such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine or fromalkali metal carbonates or bicarbonates such as potassium carbonate,sodium carbonate or sodium bicarbonate and in the absence or presence ofan alkali metal iodide such as potassium iodide or sodium iodide. Thereaction is carried out in a solvent such as acetonitrile,N,N-dimethylformamide, toluene or propan-2-ol and at a temperaturebetween the ambient temperature and the reflux temperature of thesolvent.

Where appropriate, in step b1) or in step b2), the hydroxyl or aminefunctions present in R₃ are deprotected in accordance with theconventional methods well known to the person skilled in the art.

In one version of the process and when R₃ represents a group —CH₂NR₁₂R₁₃in which R₁₂ and R₁₃ each represent hydrogen

a3) a compound of formula

in which R₁, R₂ and R₃ are as defined for a compound of formula (I) andHal represents a halogen atom, preferably chlorine or bromine, isreacted with a compound of formula

in which p and R₄ are as defined for a compound of formula (I), to givea compound of formula

b3) the cyano group of the compound of formula (Ia) is reduced to give acompound of formula (I) in which R₃═CH₂NH₂.

Where appropriate the compound of formula (I) is converted into one ofits addition salts with an acid.

In step a3) the reaction between the compound of formula (IIc) or (IId)and the compound of formula (III) is carried out as described above instep a1) or a2) of the process according to the invention.

In step b3) the reduction of the cyano group of the compound of formula(Ia) is carried out in accordance with conventional methods. Thus, forexample, the reduction is carried out by hydrogenation in the presenceof a catalyst such as Raney® nickel or rhodium on alumina and in thepresence or absence of ammonia in a solvent such as methanol,N,N-dimethylformamide or tetrahydrofuran or a mixture of these solventsand at a temperature between ambient temperature and 60° C.

In another version of the process and when R₃ constitutes a double bondbetween the carbon atom to which it is attached and the adjacent carbonatom of the piperidine ring a compound of formula

in which R₁, R₂, n, p and R₄ are as defined for a compound of formula(I) is dehydrated to give a compound of formula

Where appropriate the compound of formula (I) is converted into one ofits addition salts with an acid.

The dehydration is carried out using for example an aceticacid/hydrochloric acid mixture or an acetic acid/sulphuric acid mixtureat a temperature between the ambient temperature and 140° C. Thereaction can also be carried out using p-toluenesulphonic acid, in asolvent such as toluene and at a temperature between the ambienttemperature and the reflux temperature.

A compound of formula (I) in which R₃ represents a group —CH₂NR₁₂R₁₃ inwhich R₁₂═H and R₁₃═(C₁-C₅)alkyl may also be prepared by reacting acompound of formula (I) in which R₃═—CH₂NH₂ with a (C₁-C₅)alkyl halidein the presence of a base such as an alkali metal carbonate such aspotassium carbonate in a solvent such as acetonitrile,N,N-dimethylformamide or tetrahydrofuran at a temperature between theambient temperature and the reflux temperature of the solvent. Anidentical reaction is used to prepare the compounds of formula (I) inwhich R₁₂ et R₁₃ each represent the same or a different (C₁-C₅)alkyl.

A compound of formula (I) in which R₃ represents a group —CH₂NR₁₂R₁₃ inwhich R₁₂═H or (C₁-C₅)alkyl and R₁₃═(C₁-C₅)alkyl, a group —(CH₂)_(q)—OHor a group —(CH₂)_(q)—S—CH₃ respectively may also be prepared byreacting a compound of formula (I) in which R₃═—CH₂—NHR₁₂ withformaldehyde or with an aldehyde of formula OHC—(C₁-C₄)alkyl,OHC—(CH₂)_(q-1)—OH or OHC—(CH₂)_(q-1)—S—CH₃ respectively, or with acorresponding ketone, in the presence of a reducing agent such as sodiumborohydride or sodium triacetoxyborohydride and in the presence of anacid such as acetic acid in a solvent such as dichloromethane ortetrahydrofuran at a temperature between 0° C. and the ambienttemperature.

A compound of formula (I) in which R₃ represents a group —CH₂NR₁₂R₁₃ inwhich R₁₂ et R₁₃, together with the nitrogen atom to which they areattached, constitute aziridine may also be prepared by cyclizing acorresponding intermediate in which R₃ represents a group—CH₂NH—CH₂CH₂—Cl in the presence of a base such as an alkali metalcarbonate such as potassium carbonate and in the presence of an alkalimetal iodide such as potassium iodide in a solvent such as acetonitrileand at a temperature between the ambient temperature and the refluxtemperature of the solvent; the corresponding intermediate is preparedby reacting a compound of formula (I) in which R₃═—CH₂NH₂ withchloroacetaldehyde by the method described above.

A compound of formula (I) in which R₃ represents a group —CH₂NR₁₂R₁₃ inwhich R₁₂ and R₁₃, together with the nitrogen atom to which they areattached, constitute azetidine, pyrrolidine, piperidine or morpholine,respectively, may also be prepared by reacting a compound of formula (I)in which R₃═—CH₂NH₂ with a compound of formula Hal-(CH₂)₃-Hal,Hal-(CH₂)₄-Hal, Hal-(CH₂)₅-Hal or Hal-CH₂CH₂—O—CH₂CH₂-Hal respectively,in which Hal represents a halogen atom, preferably chlorine or bromine,in the presence of a base such as an alkali metal carbonate such aspotassium carbonate or in the presence of an alkali metal iodide such aspotassium iodide in a solvent such as acetonitrile, ethylene glycol or amixture of these solvents and at a temperature between the ambienttemperature and the reflux temperature of the solvent.

A compound of formula (I) in which R₃ represents a group—CH₂NR₈CONR₁₄R₁₅ in which R₈═R₁₄═R₁₅═H may also be prepared by reactinga compound of formula (I) in which R₃═—CH₂NH₂ with trimethylsilylisocyanate in a solvent such as dichloromethane at a temperature betweenthe ambient temperature and the reflux temperature of the solvent,followed by hydrolysis in an acidic medium.

A compound of formula (I) in which R₃ represents a group —CONR₁₆R₁₇ mayalso be prepared by reacting a corresponding intermediate in which R₃represents a carboxyl with a compound of formula HNR₁₆R₁₇ byconventional methods of peptide coupling; the corresponding intermediateis prepared by conventional methods by acid or base treatment of acompound of formula (I) in which R₃ represents a (C₁-C₄)alkoxycarbonylor by reacting a compound of formula (Ia) with a strong base such as analkali metal hydroxide such as potassium hydroxide in a solvent such astoluene or ethylene glycol at a temperature between the ambienttemperature and the reflux temperature of the solvent.

A compound of formula (I) in which R₃ represents a group —NR₈COR₉ inwhich R₉═—(CH₂)_(m)—NR₆R₇ may also be prepared by reacting acorresponding intermediate in which R₃ represents a group—NR₈CO(CH₂)_(m)-Hal and Hal represents a halogen atom, preferablychlorine, with an excess of a compound of formula HNR₆R₇ in a solventsuch as dichloromethane or ethanol at a temperature between the ambienttemperature and the reflux temperature of the solvent; the correspondingintermediate is prepared by reacting a compound of formula (I) in whichR₃═—NHR₈ with a compound of formula Hal-CO—(CH₂)_(m)-Hal in which Halrepresents a halogen atom, preferably chlorine or bromine, in thepresence of a base such as triethylamine or N,N-diisopropylethylamine ina solvent such as dichloromethane and at a temperature between 0° C. andthe ambient temperature.

A compound of formula (I) in which R₃ represents a group —CH₂OR₅ inwhich R₅ represents a hydrogen atom may also be prepared by acid or basetreatment of a compound of formula (I) in which R₃ represents a group—CH₂OR₅ in which R₅ represents a (C₁-C₄)alkylcarbonyl.

The compounds of formula (I) thus obtained may be subsequently separatedfrom the reaction medium and purified by conventional methods, forexample by crystallization or chromatography.

The compounds of formula (I) thus obtained are isolated in the form ofthe free base or a salt, by conventional techniques.

The compounds of formula (IIa) are prepared by reacting a piperidinederivative of formula

in which R₁, R₂ and R₃ are as defined for a compound of formula (I) witha compound of formula

in which Hal and Hal′ represent each independently a halogen atom,preferably chlorine or bromine. The reaction is carried out in thepresence of a base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine in a solvent such as dichloromethane, chloroform,tetrahydrofuran, dioxane or a mixture of these solvents and at atemperature between 0° C. and the ambient temperature.

The compounds of formula (IIb) are prepared by reacting the compound offormula (IV) with a compound of formula

in which Hal and Hal′ are as defined above under the operatingconditions mentioned above.

Similarly the compounds of formula (IIc) or (IId) respectively areprepared by reacting a compound of formula

in which R₁ and R₂ are as defined for a compound of formula (I) with acompound of formula (V) or (VI) respectively in accordance with the sameoperating conditions as above.

The compounds of formula (V) or (VI) are available commercially, areknown or are prepared by known methods.

The compounds of formula (III) are available commercially or areprepared by known methods such as those described in J. Org. Chem.,1953, 18, 1484-1488, J. Med. Chem., 1978, 21 (6), 536-542, Chem. Pharm.Bull., 1991, 39 (9), 2288-2300, Tetrahedron Letters, 1998, 39, 617-620or in WO 97/28129.

For example, a compound of formula (III) is prepared by reacting acompound of formula

in which p is as defined for a compound of formula (I) and W representshydrogen or an N-protective group with a compound of formulaHal-R₄  (VIII)in which R₄ is as defined for a compound of formula (I) and Halrepresents a halogen atom, preferably chlorine, bromine or iodine.

The reaction is carried out in the presence or absence of a base, in aninert solvent such as ethanol, propan-2-ol, n-butanol, acetonitrile ortoluene at a temperature between 0° C. and the reflux temperature of thesolvent. When a base is used it is selected from organic bases such asdiisopropylethylamine or from alkali metal carbonates such as sodium orpotassium carbonate. In the absence of a base the reaction is carriedout using an excess of the compound of formula (VII). The reaction mayalso be carried out without solvent, by heating the mixture of compounds(VII) and (VIII) at temperatures of the order of from 140° C. to 180° C.

Where appropriate, when W represents an N-protective group, it iseliminated by conventional methods to give the expected compounds offormula (III).

The compounds of formula (VII) or of formula (VIII) are known or areprepared by known methods.

The compounds of formula (IV) are available commercially, are known orare prepared by known methods such as those described in EP-0 474 561,EP-0 673 928 or WO 96/23787.

The compounds of formula (IV) are generally prepared in a form in whichthey are protected on the nitrogen atom of the piperidine; after a stepof deprotection the compounds of formula (IV) themselves are obtained.

In particular a compound of formula (IV) in which R₃ represents a group—OR₅ in which R₅═H is prepared by reacting an organomagnesium derivativeof formula

in which R₁ and R₂ are as defined for a compound of formula (I) and Halrepresents a halogen atom, preferably bromine, with1-benzyl-4-piperidinone in a solvent such as diethyl ether ortetrahydrofuran at a temperature between the ambient temperature andreflux temperature of the solvent.

The organomagnesium derivatives of formula (IX) are prepared byconventional methods well known to the person skilled in the art fromthe corresponding halogenated derivatives.

From compounds of formula (IV) in which R₃═—OH the compounds of formula(IV) in which R₃═—OR₅ in which R₅ represents a (C₁-C₄)alkyl or a(C₁-C₄)alkylcarbonyl, respectively, are prepared by an alkylation oracylation reaction, respectively, by methods which are known to theperson skilled in the art.

The compounds of formula (IV) in which R₃═—OH and which carry aprotective group on the nitrogen atom of the piperidine may undergo aRitter reaction by the action of acetonitrile in an acidic medium inorder to prepare the compounds of formula (IV) in which R₃═—NHCOCH₃ bythe method described in EP-0 474 561. Hydrolysis in a strong acidicmedium is then used to prepare the compounds of formula (IV) in whichR₃═—NR₆R₇ in which R₆═R₇═H. The methods described in EP-0 673 928 or WO96/23787 are used to prepare the compounds of formula (IV) in whichR₃═—NR₆R₇ in which R₆ and/or R₇ represents a (C₁-C₄)alkyl.

The compounds of formula (IV) in which R₃═—NR₈COR₉ in which R₉ is a(C₁-C₄)alkyl, or else R₃═—NR₈CONR₁₀R₁₁, or else R₃═—CH₂NR₁₂R₁₃ in whichR₁₂ and R₁₃ represent each independently a hydrogen or a (C₁-C₄)alkyl,or else R₃═—CH₂NR₈CONR₁₄R₁₅, or else R₃═(C₁-C₄)alkoxycarbonyl, or elseR₃═—CONR₁₆R₁₇ are prepared by the methods described in WO 96/23787.

A compound of formula (IV) in which R₃═—CH₂NR₁₂R₁₃ in which R₁₂═R₁₃═H isprepared from the compound of formula (IVa) by the method describedabove for a compound of formula (I).

A compound of formula (IV) in which R₃═—NR₈COR₉ in whichR₉═—(CH₂)_(m)NR₆R₇ is prepared by the method described above for acompound of formula (I).

A compound of formula (IV) in which R₃═—CH₂NR₁₂R₁₃ in which R₁₂═H or(C₁-C₅)alkyl and R₁₃═(C₁-C₅)alkyl, a group —(CH₂)_(q)—OH or a group—(CH₂)_(q)—S—CH₃ is prepared by the method described above for acompound of formula (I).

A compound of formula (IV) in which R₃═—CH₂NR₁₂R₁₃ in which R₁₂═H andR₁₃═—CH₃ may also be prepared by reducing a corresponding intermediatein which R₃═—CH₂NHCHO using a reducing agent such as lithium aluminiumhydride in a solvent such as ether or tetrahydrofuran at a temperaturebetween the ambient temperature and the reflux temperature of thesolvent. The corresponding intermediate is prepared by reacting acompound of formula (IV) in which R₃═—CH₂NH₂ with ethyl formate at atemperature between the ambient temperature and 60° C.

A compound of formula (IV) in which R₃═—CH₂NR₁₂R₁₃ in which R₁₂ and R₁₃,together with the nitrogen atom to which they are attached, constituteaziridine, azetidine, pyrrolidine, piperidine or morpholine is preparedby the methods described above for a compound of formula (I).

A compound of formula (IV) in which R₃═—CONR₁₆R₁₇ in which R₁₆═R₁₇═H mayalso be prepared by reacting a compound of formula (IVa), protected onthe nitrogen atom of the piperidine, with hydrogen peroxide in thepresence of a strong base such as an alkali metal hydroxide such assodium hydroxide and a phase transfer catalyst such as a substitutedquaternary ammonium salt, triethylammonium chloride for example, in asolvent such as toluene in a mixture with water, at a temperaturebetween the ambient temperature and the reflux temperature of thesolvent.

The compounds of formula (IVa) are prepared by known methods such asthose described in Bioorg. Med. Chem. Lett., 1999, 9, 3273-3276 and inJ. Med. Chem., 1999, 42 (23), 4778-4793.

From compounds of formula (IV) in which R₃═—CH₂OH the compounds offormula (IV) in which R₃═—CH₂OR₅ in which R₅ represents a (C₁-C₄)alkylor a (C₁-C₄)alkylcarbonyl, respectively, are prepared by an alkylationor acylation reaction, respectively, by the methods known to the personskilled in the art.

The compounds of formula (IV) in which R₃═—CH₂OR₅ in which R₅ representsa hydrogen atom are prepared by reducing a compound of formula (IV) inwhich R₃ represents a methoxycarbonyl by methods known to the personskilled in the art.

The compounds of formula (IV) in which R₃ represents a(C₁-C₄)alkoxycarbonyl are prepared by esterification reaction of acorresponding intermediate in which R₃ represents a carboxyl by methodsknown to the person skilled in the art; the corresponding intermediateis prepared by reacting a compound of formula (VIa) with a strong basesuch as an alkali metal hydroxide such as potassium hydroxide, in asolvent such as toluene or ethylene glycol at a temperature between theambient temperature and the reflux temperature of the solvent.

During any of the steps of preparing the compounds of formula (I), or ofthe intermediates of formula (Ia), (IIa), (IIb), (IIc), (IId), (III) or(IV), it may be necessary and/or desirable to protect the sensitive orreactive functional groups, such as the amine, hydroxyl or carboxylgroups, which are present on any of the molecules concerned. Thisprotection may be carried out using the conventional protective groups,such as those described in Protective Groups in Organic Chemistry, J. F.W. McOmie, Ed., Plenum Press, 1973, in Protective Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, Ed., John Wiley & Sons, 1991or in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag. Theprotective groups can be eliminated in an appropriate subsequent step,using the methods which are known to the person skilled in the art andwhich are not to the detriment of the rest of the molecule in question.

The N-protective groups used where appropriate are conventionalN-protective groups which are well known to the person skilled in theart, such as, for example, the tert-butoxycarbonyl,fluorenylmethoxycarbonyl, benzyl, benzhydrylidene or benzyloxycarbonylgroup.

The invention, in another of its aspects, further provides the compoundsof formula (Ia). These compounds are useful as synthesis intermediatesfor the compounds of formula (I).

Accordingly, in another of its aspects, the invention provides compoundsof formula

in which

-   -   n is 1 or 2;    -   p is 1 or 2;    -   R₁ represents a halogen atom; a trifluoromethyl radical; a        (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethoxy radical;    -   R₂ represents a hydrogen atom or a halogen atom;    -   R₄ represents an aromatic group selected from

-   -   the said aromatic groups being unsubstituted or mono- or        disubstituted by a substituent selected independently from a        halogen atom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethyl        radical;    -   in the form of a base or an addition salt with an acid, and in        the form of a hydrate or solvate.

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limitative andmerely illustrate the present invention. The numbers of the compoundsexemplified refer to those given in Table I below, which illustrates thechemical structures and the physical properties of some compoundsaccording to the invention.

In the preparations and in the examples the following abbreviations areused:

-   -   ether: diethyl ether    -   iso ether: diisopropyl ether    -   DMSO: dimethyl sulphoxide    -   DMF: N,N-dimethylformamide    -   THF: tetrahydrofuran    -   DCM: dichloromethane    -   AcOEt: ethyl acetate    -   DIPEA: diisopropylethylamine    -   TFA: trifluoroacetic acid    -   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   PyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium        hexafluorophosphate    -   2N hydrochloric ether: 2N solution of hydrochloric acid in        diethyl ether    -   m.p.: melting point    -   AT: ambient temperature    -   b.p.: boiling temperature    -   HPLC: high performance liquid chromatography    -   Silica H: Silica gel 60 H sold by Merck (Darmstadt)    -   Buffer solution pH=2: solution of 16.66 g of KHSO₄ and 32.32 g        of K₂SO₄ in one liter of water.

The proton magnetic resonance (¹H NMR) spectra are recorded at 200 MHzin DMSO-d₆, using the DMSO-d₆ peak as reference. The chemical shifts δare expressed in parts per million (ppm). The signals observed areexpressed as follows: s: singlet; bs: broad singlet; d: doublet; sd:split doublet; t: triplet; st: split triplet; q; quadruplet; unres.comp.: unresolved complex; mt: multiplet.

The NMR spectra confirm the structures of the compounds.

The compounds according to the invention are analysed by LC/UV/MS(liquid chromatography/UV detection/mass spectrometry) coupling.

For the compounds a check is made that their mass spectra as obtained inthe positive electrospray mode (ESI+) are compatible with the calculatedmolar mass.

The mass spectra of the compounds according to the invention generallyhave as their base peak the molecular ion MH⁺.

PREPARATIONS

1. Preparations of Compounds of Formulae (IV) and (IVa)

Preparation 1.1

4-[3-(Trifluoromethyl)phenyl]-4-piperidinol hydrochloride

(IV), HCl: R₁═3-CF₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinol hydrochloride

A mixture of 180 g of magnesium in 2670 ml of THF is heated to 30° C.and admixed with 33 ml of a solution of 1670 g of1-bromo-3-(trifluoromethyl)benzene in 1330 ml of THF and then, slowly,with the remainder of the solution so as to bring about and subsequentlymaintain reflux of the THF, and is left at reflux with stirring for 2hours. Subsequently a solution of 1000 g of 1-benzyl-4-piperidinone in3200 ml of THF is added slowly and the mixture is heated at reflux for 2hours. After cooling to AT, the reaction mixture is introduced over 30minutes into a solution of 1870 g of ammonium chloride in 6700 ml ofwater and the mixture is left with stirring at 20-25° C. for 2 hours.After decanting, the organic phase is washed with 5330 ml of water andthe solvent is evaporated under vacuum. The residue is taken up in 5330ml of ether, a solution of 210 g of HCl gas in 800 ml of propan-2-ol isadded slowly, the temperature being kept below 25° C., the mixture isleft with stirring for 40 minutes and the crystals formed are isolatedwith suction. The crystals are taken up in 2000 ml of ether and againisolated with suction. 1080 g of the expected product are obtainedfollowing recrystallization from a propan-2-ol/EtOH (70/30; v/v)mixture.

B) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinol hydrochloride

A mixture of 1000 g of the compound obtained in the preceding step and83 g of 10% palladium on carbon (50% moisture content) in 2910 ml ofEtOH and 2910 ml of MeOH is hydrogenated at 50° C. under a pressure of 2bars. The catalyst is filtered off and washed twice with 660 ml of MeOHand the filtrate and washings are concentrated under vacuum. The residueis taken up in 3320 ml of ether and is left with stirring at AT for 1hour 30 minutes. The precipitate formed is isolated with suction, washedwith 280 ml of ether and dried under vacuum at 40° C. This gives 726 gof the expected product.

Preparation 1.2

4-Methoxy-4-[3-(trifluoromethyl)phenyl]piperidine

(IV): R₁═3-CF₃; R₂═H; R₃═—OCH₃.

A) tert-Butyl4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

20 g of the compound obtained in Preparation 1.1 in 80 ml of DCM isadmixed at AT with 17.92 g of triethylamine and then, dropwise, with asolution of 16.3 g of di-tert-butyl dicarbonate in 20 ml of DCM and themixture is left with stirring at AT for 18 hours. Water is added to thereaction mixture, which is then extracted with DCM, the organic phase iswashed with water and a 5% KHSO₄ solution and dried over Na₂SO₄ and thesolvent is evaporated under vacuum. This gives 13 g of the expectedproduct following recrystallization from an iso ether/hexane mixture.

B) tert-Butyl4-methoxy-4-[3-(trifluoromethyl)phenyl]1-piperidinecarboxylate

A solution of 2 g of the compound obtained in the preceding step in 15ml of DMF and 20 ml of THF is admixed, in portions and at AT, with 0.277g of sodium hydride at a concentration of 60% in oil and the mixture isleft with stirring for 40 minutes. Subsequently 1.3 g of methyl iodideare added and the mixture is left with stirring for 2 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upwith water and extracted with AcOEt, the organic phase is washed withwater and dried over Na₂SO₄ and the solvent is evaporated under vacuum.This gives 2 g of the expected product in the form of a yellow oil.

C) 4-Methoxy-4-[3-(trifluoromethyl)phenyl]piperidine

A mixture of 2 g of the compound obtained in the preceding step and 5 mlof TFA in 15 ml of DCM is left with stirring at AT for 1 hour. Thereaction mixture is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with a 5% Na₂CO₃ solution anddried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives1.7 g of the expected product in the form of an orange-coloured oil.

Preparation 1.3

N,N-Dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine

(IV): R₁═3-CF₃; R₂═H; R₃═—N(CH₃)₂.

A) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinol

An icebath is used to cool a solution of 20 g of the compound obtainedin Preparation 1.1 (free base) and 11.3 ml of triethylamine in 200 ml ofDCM, 11 ml of benzyl bromide are added dropwise and the mixture is leftwith stirring at AT overnight. It is concentrated under vacuum, theresidue is taken up in saturated K₂CO₃ solution and extracted withAcOEt, the organic phase is washed with saturated K₂CO₃ solution andwith saturated NaCl solution and dried over Na₂SO₄ and the solvent isevaporated under vacuum. The oily residue is taken up in pentane and theprecipitate formed is isolated with suction. This gives 17 g of theexpected product.

B) N-[1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]acetamide

An icebath is used to cool 60 ml of concentrated H₂SO₄, a solution of 16g of the compound obtained in the preceding step in 120 ml ofacetonitrile is added dropwise, during which the temperature of thereaction medium is kept below 30° C. and the mixture is left withstirring overnight, during which the temperature is allowed to return toAT. The reaction mixture is poured onto ice and rendered alkaline byaddition of concentrated NaOH solution and the precipitate formed isisolated with suction. The precipitate is dissolved in DCM, the organicphase is washed with water and dried over Na₂SO₄ and the solvent isevaporated under vacuum. This gives 9.7 g of the expected productfollowing recrystallization from acetonitrile.

C) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine

A mixture of 9.6 g of the compound obtained in the preceding step, 250ml of concentrated HCl solution and 250 ml of water is heated at 150° C.overnight. Half of the reaction mixture is concentrated under vacuum,the resulting acidic aqueous phase is rendered alkaline by addition ofconcentrated NaOH solution and extracted with DCM, the organic phase isdried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives8.1 g of the expected product, which is used as it is.

D) 1-Benzyl-N,N-dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine

A mixture of 8.1 g of the compound obtained in the preceding step, 3.5ml of a 37% solution of formaldehyde in water and 10 ml of acetic acidin 250 ml of THF is admixed in portions and at AT with 50 g of sodiumtriacetoxyborohydride and the mixture is left with stirring at ATovernight. 200 ml of MeOH are added and the reaction mixture is heatedat 70° C. for 1 hour and concentrated under vacuum. The residue is takenup with 1N NaOH solution and extracted with DCM, the organic phase iswashed with water and dried over Na₂SO₄ and the solvent is evaporatedunder vacuum. This gives 8.7 g of the expected product in the form of anoil which solidifies.

E) N,N-Dimethyl-4-[3-(trifluoromethyl)phenyl]-4-piperidineamine

A mixture of 8.2 g of the compound obtained in the preceding step, 5 gof ammonium formate and 2 g of 10% palladium on carbon in 100 ml of MeOHis left with stirring at AT for 1 hour. The catalyst is filtered off andthe filtrate is concentrated under vacuum. The residue is taken up withsaturated K₂CO₃ solution and extracted with AcOEt, the organic phase isdried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives4.8 g of the expected product.

Preparation 1.4

4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride

(IVa): HCl: R₁═3-CF₃; R₂═H.

A)2-(2,2-Diethoxyethyl)-4,4-diethoxy-2-[3-(trifluoromethyl)phenyl]butanenitrile

A mixture of 30 g of 3-trifluoromethyl)phenylacetonitrile and 14.4 g ofsodium amide in 400 ml of toluene is left with stirring at AT for 5minutes, 66 ml of bromoacetaldehyde diethyl acetal are added and themixture is then heated at 60° C. for 3 hours. It is concentrated undervacuum, the residue is taken up in water and extracted with ether, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. The residue is chromatographed on silica gel H, eluting with aDCM/AcOEt (100/5; v/v) mixture. This gives 26 g of the expected product.

B) 4-Oxo-2-(2-oxoethyl)-2-[3-(trifluoromethyl)phenyl]butanenitrile

A mixture of 23.9 g of the compound obtained in the preceding step in 90ml of formic acid is left with stirring at 50° C. for 1 hour. Water isadded to the reaction mixture, which is then extracted with AcOEt, theorganic phase is washed with water and with 10% NaHCO₃ solution anddried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives16 g of the expected product, which is used immediately in the followingstep.

C) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochloride

A mixture of 16 g of the compound obtained in the preceding step, 6.25ml of benzylamine, 48.6 g of sodium triacetoxyborohydride and 5 drops ofacetic acid in 150 ml of DCM is left with stirring at AT overnight.Subsequently 40 ml of MeOH are added dropwise and the mixture is thenheated at 60° C. for 1 hour. The reaction mixture is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedwith 10% NaHCO₃ solution and with water and dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is taken up in asaturated solution of HCl gas in ether and the precipitate formed isisolated with suction. This gives 18 g of the expected product.

D) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride

A mixture of 2 g of the compound obtained in the preceding step and 0.2g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at AT atatmospheric pressure for 3 hours. The catalyst is filtered off onCelite® and the filtrate is concentrated under vacuum. This gives 1.5 gof the expected product.

This compound can also be prepared by following the three steps below:

A′) tert-Butyl bis(2-chloroethyl)carbamate

A mixture of 106 g of N,N-bis(2-chloroethyl)amine hydrochloride and 130g of di-tert-butyl dicarbonate in 1 500 ml of DCM is admixed dropwiseover 1 hour 30 minutes at AT with 83 ml of triethylamine, then left withstirring at AT overnight. The reaction mixture is washed with water andthe organic phase is dried over Na₂SO₄ and evaporated under vacuum. Thisgives 150 g of the expected product, which is used as it is.

B′) tert-Butyl 4-cyano-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

A suspension of 56 g of sodium hydride at a concentration of 60% in oilin 750 ml of DMSO and 250 ml of THF is admixed dropwise under an inertatmosphere and at AT with a solution of 120 g of3-(trifluoromethyl)phenylacetonitrile in 250 ml of DMSO and then, slowlywith a solution of 150 g of the compound obtained in the preceding stepin 250 ml of DMSO and heated at 60° C. overnight. The reaction mixtureis poured into an ice/H₂O mixture and extracted with ether, the organicphase is washed with water and with saturated NaCl solution and driedover Na₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with aDCM/AcOEt (80/20; v/v) mixture. This gives 191 g of the expectedproduct, which crystallizes; m.p.=72-73° C.

C′) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride

A mixture of 115 g of the compound obtained in the preceding step, 500ml of a 2N solution of HCl in ether and 150 ml of MeOH is left withstirring at AT for 4 hours. The crystalline product formed is isolatedwith suction and dried. This gives 75 g of the expected product,m.p.=259° C.

Preparation 1.5

tert-Butyl [4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate

(IV): R₁═3-CF₃; R₂═H; R₃═—CH₂NH—COOC(CH₃)₃.

A) [1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylamine

A mixture of 1.5 g of the compound obtained in step C of preparation1.4, 0.15 g of Raney® nickel and 5 ml of aqueous ammonia in 20 ml ofMeOH is hydrogenated at AT under atmospheric pressure overnight. Thecatalyst is filtered off and the filtrate is concentrated under vacuum.This gives 1.45 g of the expected product.

B) tert-Butyl[1-benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate

A mixture of 1.45 g of the compound obtained in the preceding step and20 ml of AcOEt is heated to 40° C., 0.9 g of di-tert-butyl dicarbonateis added and the mixture is then heated at reflux for 30 minutes. Aftercooling to AT it is admixed with water and extracted with AcOEt, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 1.86 g of the expected product.

C) tert-Butyl [4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate

A mixture of 1.8 g of the compound obtained in the preceding step and0.18 g of 10% palladium on carbon in 20 ml of MeOH is hydrogenated at ATat atmospheric pressure overnight. The catalyst is filtered off and thefiltrate is concentrated under vacuum. This gives 1.3 g of the expectedproduct in the form of an oil.

Preparation 1.6

4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarboxamide

(IV): R₁═3-CF₃; R₂═H; R₃═—CONH₂.

A) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide

A mixture of 5 g of the compound obtained in step C of preparation 1.4,30 ml of toluene, 30 ml of 30% H₂O₂ solution, 30 ml of 30% NaOH solutionand 0.5 g of aliquot 336 (trioctylmethylammonium chloride) is heated at100° C. for 48 hours. It is concentrated under vacuum, the residue istaken up in water and extracted with DCM, the organic phase is driedover Na₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel H, eluting with a DCM/MeOH (100/3; v/v)mixture. This gives 2.5 g of the expected product.

B) 4-[3-(Trifluoromethyl)phenyl]-4-piperidinecarboxamide

A mixture of 2.5 g of the compound obtained in the preceding step and0.25 g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at ATunder atmospheric pressure for 48 hours. The catalyst is filtered offand the filtrate is concentrated under vacuum. This gives 1.7 g of theexpected product.

Preparation 1.7

4-[2-(Trifluoromethyl)phenyl]-4-piperidinol

(IV): R₁═2-CF₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-[2-(trifluoromethyl)phenyl]-4-piperidinol

A mixture of 1.52 g of magnesium in 25 ml of THF is admixed dropwiseover 20 minutes with a solution of 14.25 g of1-bromo-2-(trifluoromethyl)benzene in 15 ml of THF and the mixture isheated at reflux for 30 minutes. After it has cooled on an ice bath, itis admixed slowly with a solution of 10 g of 1-benzyl-4-piperidinone in30 ml of THF and left with stirring at AT for 3 hours. The reactionmixture is poured into saturated aqueous ammonium chloride solution andextracted with AcOEt, the combined organic phases are washed with waterand dried over Na₂SO₄ and the solvents are evaporated under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/AcOEt(70/30; v/v) mixture. This gives 4.5 g of the expected product.

B) 4-[2-(Trifluoromethyl)phenyl]-4-piperidinol

A mixture of 4.5 g of the compound obtained in the preceding step and0.5 g of 10% palladium on carbon in 100 ml of MeOH is hydrogenated at35° C. under atmospheric pressure overnight. The catalyst is filteredoff and the filtrate is concentrated under vacuum. This gives 2.7 g ofthe expected product following recrystallization from iso ether.

Preparation 1.8

4-[2-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride

(IVa): HCl: R₁═2-CF₃; R₂═H.

A) tert-Butyl4-cyano-4-[2-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

A suspension of 9 g of sodium hydride at a concentration of 60% in oilin 125 ml of DMSO and 125 ml of THF is admixed dropwise and at AT with asolution of 20 g of 2-(trifluoromethyl)phenylacetonitrile in 50 ml ofDMSO and then, slowly, with a solution of 25 g of the compound obtainedin step A′ of preparation 1.4 in 70 ml of DMSO and the mixture is heatedat 60° C. for 24 hours. The reaction mixture is poured into 2 liters ofwater and extracted with ether, the organic phase is washed with waterand dried over Na₂SO₄ and the solvent is evaporated under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/AcOEt (70/30; v/v) mixture. This gives 16 g of the expectedproduct.

B) 4-[2-(Trifluoromethyl)phenyl]-4-piperidinecarbonitrile hydrochloride

A mixture of 6 g of the compound obtained in the preceding step, 150 mlof 2N hydrochloric ether and 20 ml of MeOH is left with stirring at ATfor 2 hours. It is concentrated under vacuum, the residue is taken up inether and the precipitate formed is isolated with suction. This gives2.3 g of the expected product.

Preparation 1.9

Methyl 4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylatehydrochloride

(IV): HCl: R₁═3-CF₃; R₂═H; R₃═—COOCH₃.

A) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylic acid

A mixture of 5 g of the compound obtained in step C of preparation 1.4and 4.25 g of KOH pellets in 80 ml of ethylene glycol is heated atreflux for 3 hours. It is cooled to AT and admixed with 100 ml of water,acidified to pH=6.5 by addition of 10% HCl solution, and the precipitateformed is isolated with suction and dried under vacuum. This gives 3.9 gof the expected product, m.p.=243° C.

B) Methyl 1-benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylatehydrochloride

A mixture of 3 g of the compound obtained in the preceding step and 50ml of thionyl chloride in 100 ml of DCM is heated at 60° C. for 3 hours.It is concentrated under vacuum and the residue is taken up in 100 ml ofMeOH and heated at 60° C. overnight. Concentration under vacuum gives 4g of the expected product, m.p.=230° C.

C) Methyl 4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylatehydrochloride

A mixture of 4 g of the compound obtained in the preceding step and 0.4g of 10% palladium on carbon in 200 ml of MeOH is hydrogenated at ATunder atmospheric pressure overnight. The catalyst is filtered off andthe filtrate is concentrated under vacuum. This gives 2.5 g of theexpected product.

Preparation 1.10

[4-[3-(Trifluoromethyl)phenyl]-4-piperidyl]methyl acetate

(IV): R₁═3-CF₃; R₂═H; R₃═—CH₂—O—CO—CH₃.

A) 1-(tert-Butyl)-4-methyl4-[3-(trifluoromethyl)phenyl]-1,4-piperidinedicarboxylate

A mixture of 7 g of the compound obtained in preparation 1.9, 5.33 g ofdi-tert-butyldicarbonate and 3.5 ml of triethylamine in 100 ml of DCM isleft with stirring at AT for 2 hours. It is concentrated under vacuum,the residue is taken up in water and extracted with ether, the organicphase is washed with water and dried over Na₂SO₄ and the solvent isevaporated under vacuum. This gives 9.3 g of the expected product.

B) tert-Butyl4-(hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

A mixture of 9.27 g of the compound obtained in the preceding step in150 ml of ether is cooled to 0° C., 1 g of lithium aluminium hydride isadded and the mixture is left with stirring at 0° C. for 4 hours. Thereaction mixture is admixed with saturated NH₄Cl solution, the mineralsalts are filtered off, the filtrate is extracted with AcOEt, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 5.5 g of the expected product followingrecrystallization from ether.

C) tert-Butyl4-[(acetyloxy)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

A mixture of 5.5 g of the compound obtained in the preceding step and 2ml of triethylamine in 50 ml of DCM is cooled to −70° C., 1.1 ml ofacetyl chloride are added and the mixture is left with stirringovernight, during which the temperature is allowed to return to AT. Iceis added to the reaction mixture, which is then extracted with DCM, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 6 g of the expected product.

D) [4-[3-(Trifluoromethyl)phenyl]-4-piperidyl]methyl acetate

A mixture of 6 g of the compound obtained in the preceding step and 30ml of TFA in 50 ml of DCM is left with stirring at AT for 1 hour. It isconcentrated under vacuum, the residue is taken up with ice and thenwith 10% NaHCO₃ solution and extracted with DCM, the organic phase isdried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives4.5 g of the expected product.

Preparation 1.11

4-[4-(Trifluoromethyl)phenyl]-4-piperidinol

(IV): R₁═4-CF₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-[4-(trifluoromethyl)phenyl]-4-piperidinol

This compound is prepared by the procedure described in step A ofpreparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of14.25 g of 1-bromo-4-(trifluoromethyl)benzene in 15 ml of THF and asolution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF. This gives7.3 g of the expected product.

B) 4-[4-(Trifluoromethyl)phenyl]-4-piperidinol

A mixture of 4.8 g of the compound obtained in the preceding step and 2g of 10% palladium on carbon in 50 ml of MeOH is hydrogenated at 30° C.under atmospheric pressure for 2 hours. The catalyst is filtered off andthe filtrate is concentrated under vacuum. This gives 2.4 g of theexpected product following recrystallization from iso ether.

Preparation 1.12

4-(4-Chlorophenyl)-4-piperidinecarbonitrile hydrochloride

(IVa), HCl: R₁═4-Cl; R₂═H.

A) tert-Butyl 4-(4-chlorophenyl)-4-cyano-1-piperidinecarboxylate

A suspension of 4.4 g of sodium hydride at a concentration of 60% in oilin 300 ml of THF is admixed rapidly at AT with 7.51 g of4-chlorophenylacetonitrile and then with 12 g of tert-butylbis(2-chloroethyl)carbamate, heated at 40° C. for 28 hours and then leftwith stirring at AT overnight. Saturated ammonium chloride solution isadded to the reaction mixture, which is then concentrated under vacuumto remove the THF, after which the aqueous phase which remains isextracted with ether, the organic phase is washed with a buffer solutionpH=2 and with saturated NaCl solution and dried over Na₂SO₄ and thesolvent is evaporated under vacuum. This gives 12 g of the expectedproduct, which is used as it is.

B) 4-(4-Chlorophenyl)-4-piperidinecarbonitrile hydrochloride

A mixture of 18 g of the compound obtained in the preceding step in 100ml of MeOH and 20 ml of concentrated HCl solution is heated at 40-50° C.for 3 hours. The reaction mixture is concentrated under vacuum, theresidue is taken up twice in MeOH and each time the solvent isevaporated under vacuum. This gives 5.85 g of the expected productfollowing recrystallization from acetone.

Preparation 1.13

4-(3-Methylphenyl)-4-piperidinol

(IV): R₁═3-CH₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-(3-methylphenyl)-4-piperidinol

This compound is prepared by the procedure described in step A ofpreparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of11 g of 3-bromotoluene in 15 ml of THF and a solution of 10 g of1-benzyl-4-piperidone in 30 ml of THF. The product obtained ischromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v)mixture. This gives 14.5 g of the expected product.

B) 4-(3-Methylphenyl)-4-piperidinol

A mixture of 14.5 g of the compound obtained in the preceding step and 2g of 10% palladium on carbon in 500 ml of MeOH is hydrogenated at 25° C.under atmospheric pressure for 48 hours. The catalyst is filtered offand the filtrate is concentrated under vacuum. This gives 8.9 g of theexpected product.

Preparation 1.14

4-(3-Methoxyphenyl)-4-piperidinol

(IV): R₁═3-OCH₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-(3-methoxyphenyl)-4-piperidinol

This compound is prepared by the procedure described in step A ofpreparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of12 g of 3-bromoanisole and 15 ml of THF and a solution of 10 g of1-benzyl-4-piperidone in 30 ml of THF. The product obtained ischromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 95/5;v/v) mixture. This gives 13.7 g of the expected product.

B) 4-(3-Methoxyphenyl)-4-piperidinol

A mixture of 13.7 g of the compound obtained in the preceding step and 2g of 10% palladium on carbon in 500 ml of EtOH is hydrogenated at 25° C.under atmospheric pressure for 48 hours. The catalyst is filtered offand the filtrate is concentrated under vacuum. This gives 10.8 g of theexpected product.

Preparation 1.15

N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]acetamidehydrochloride

(IV), HCl: R₁═3-CF₃; R₂═4-Cl; R₃═—NHCOCH₃.

A) 1-Benzyl-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol

A mixture of 15 g of4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 8.3 g of K₂CO₃ and7.18 ml of benzyl bromide in 80 ml of DMF is left with stirring at ATfor 2 days. The reaction mixture is poured into water and extracted withAcOEt, an insoluble product is filtered off, the organic phase is washedwith water and with saturated NaCl solution and dried over Na₂SO₄ andthe solvent is evaporated under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. This gives14.6 g of the expected product.

B)N-[1-Benzyl-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]acetamide

An ice bath is used to cool 30 ml of concentrated H₂SO₄, a solution of7.98 g of the compound obtained in the preceding step in 60 ml ofacetonitrile is added dropwise at a temperature of less than 15° C. andthe mixture is left with stirring at 15° C. for 2 days. The reactionmixture is poured onto ice, rendered alkaline by addition of NaOHpellets and extracted with AcOEt, the organic phase is dried over Na₂SO₄and the solvent is evaporated under vacuum to give an impure solid (7.86g). The residue is chromatographed on silica gel, eluting with aDCM/MeOH (97/3 to 95/5; v/v) mixture. This gives 4.26 g of the expectedproduct following recrystallization from a DCM/iso ether mixture;m.p.=198-199° C.

C) N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]acetamidehydrochloride

A mixture of 3.1 g of the compound obtained in the preceding step, and1.05 g of K₂CO₃ in 25 ml of DCM is left with stirring at AT for 15minutes, then cooled with an ice bath, admixed dropwise with a solutionof 1.2 ml of 1-chloroethyl chloroformate in 5 ml of DCM and left withstirring at 4° C. for 2 hours. An insoluble product is filtered off, thefiltrate is concentrated under vacuum, the residue is taken up in MeOHand the solvent is evaporated under vacuum. The residue is taken up with80 ml of MeOH and heated at reflux for 15 minutes and the solvent isevaporated under vacuum. This gives 2.7 g of the expected product.

D) tert-Butyl4-(acetylamino)-4-[4-chloro-3-(trifluoromethyl)phenyl]-1-piperidinecarboxylate

A mixture of 2.7 g of the compound obtained in the preceding step, 1.9ml of DIPEA and 1.64 g of di-tert-butyl dicarbonate in 20 ml of DCM isleft with stirring at AT for 2 hours. The mixture is concentrated undervacuum and the residue is chromatographed on silica gel, eluting with aDCM/MeOH (98/2; v/v) mixture. This gives 1.4 g of the expected product.

E) N-[4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]acetamidehydrochloride

A suspension of 1.4 g of the compound obtained in the preceding step in20 ml of dioxane is admixed with 4 ml of 2N hydrochloric ether solutionand left with stirring at AT for 2 hours. The reaction mixture isconcentrated under vacuum to give the expected product, which is used asit is.

Preparation 1.16

4-[3-(Trifluoromethoxy)phenyl]-4-piperidinol hydrochloride

(IV), HCl: R₁═3-OCF₃; R₂═H; R₃═—OH.

A) 1-Benzyl-4-[3-(trifluoromethoxy)phenyl]-4-piperidinol hydrochloride

This compound is prepared by the procedure described in step A ofpreparation 1.7, from 2 g of magnesium in 25 ml of THF, a solution of 20g of 1-bromo-3-(trifluoromethoxy)benzene in 15 ml of THF and a solutionof 13 g of 1-benzyl-4-piperidone in 30 ml of THF. The hydrochloride ofthe product obtained is formed in 2N hydrochloric ether solution. Thisgives 24.4 g of the expected product.

B) 4-[3-(trifluoromethoxy)phenyl]4-piperidinol hydrochloride

A mixture of 24 g of the compound obtained in the preceding step, 16 gof ammonium formate and 2 g of 10% palladium on carbon in 500 ml of MeOHis left with stirring at AT for 4 hours. The catalyst is filtered offand the filtrate is concentrated under vacuum. The residue is taken upwith saturated K₂CO₃ solution and extracted with ether, the organicphase is washed with saturated NaCl solution and dried over Na₂SO₄ andthe solvent is evaporated under vacuum. The residue is taken up with 2Nhydrochloric ether solution and the precipitate formed is isolated withsuction. This gives 6.2 g of the expected product, m.p.=145-146° C.

Preparation 1.17

tert-Butylmethyl[[4-[3-(trifluoromethyl)phenyl]piperidin-4-yl]methyl]carbamate

(IV): R₁═3-CF₃; R₂═H; R₃═—CH₂N(CH₃)—COOC(CH₃)₃.

A) N,N-Bis(2-chloroethyl)benzylamine

An ice bath is used to cool a mixture of 150 g ofN,N-bis(2-chloroethyl)amine hydrochloride and 100 ml of benzyl bromidein 1 000 ml of DMF and then 120 ml of triethylamine are added dropwiseand the mixture is left with stirring at AT overnight. The reactionmixture is concentrated under vacuum, the residue is taken up in waterand extracted 3 times with ether, the organic phases are dried overNa₂SO₄ and the solvent is evaporated under vacuum. This gives 113 g ofthe expected product.

B) 1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrilehydrochloride

A suspension of 23.24 g of sodium hydride at a concentration of 60% inoil in 100 ml of DMSO and 100 ml of THF is admixed dropwise under aninert atmosphere and at AT with a solution of 50 g of3-(trifluoromethyl)phenylacetonitrile in 150 ml of DMSO and the mixtureis left with stirring for 15 minutes. A solution of 62.43 g of thecompound obtained in the preceding step in 150 ml of DMSO issubsequently added over 1 hour and the mixture is left with stirring atAT overnight. An ice/water mixture is added, the system is extractedwith ether, the organic phase is dried over Na₂SO₄ and the solvent isevaporated under vacuum. The residue is taken up in 1 000 ml of hotEtOH, the system is left with stirring at AT for 48 hours and thecrystalline product formed is isolated with suction. This gives 50 g ofthe expected product.

C) [1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylamine

30 g of the compound obtained in the preceding step are dissolved in 10%NaOH solution and extracted with ether, the organic phase is dried overNa₂SO₄ and the solvent is evaporated under vacuum. The product, in theform of the free base, is taken up in 500 ml of MeOH and 30 ml of 20%aqueous ammonia solution, 3 g of Raney® nickel are added and the systemis hydrogenated at AT under atmospheric pressure overnight. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with AcOEt, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated under vacuum. Thisgives 27 g of the expected product.

D) [[1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]formamide

A mixture of 27 g of the compound obtained in the preceding step and 300ml of ethyl formate is left with stirring at AT overnight, then heatedat 60° C. for 6 hours and left with stirring at AT for 48 hours. It isconcentrated under vacuum, the residue is taken up with 10% HClsolution, the acidic aqueous phase is washed with ether, ice is addedand the mixture is rendered alkaline by addition of 10% NaOH solutionand extracted with ether, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel H, eluting with DCM and then with a DCM/MeOH (100/4; v/v)mixture. This gives 20 g of the expected product.

E)[[1-Benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]methylamine

A suspension of 4 g of lithium aluminium hydride in 400 ml of ether isadmixed at AT with 20 g of the compound obtained in the preceding stepand then left with stirring at AT for 16 hours. Subsequently, insuccession, 3 ml of water, 3 ml of 30% NaOH and 1 ml of water are addedand the mixture is left with stirring. The mineral salts are filteredoff on Celite, the filtrate is decanted, the organic phase is dried overNa₂SO₄ and the solvent is evaporated under vacuum. This gives 18 g ofthe expected product.

F) tert-Butyl[[1-benzyl-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]methylcarbamate

A mixture of 18 g of the compound obtained in the preceding step and 9.6g of di-tert-butyl dicarbonate in 300 ml of DCM is left with stirring atAT for 1 hour. Water is added to the reaction mixture, which is thenextracted with DCM, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel H, eluting with a DCM/MeOH (100/2; v/v) mixture. This gives21 g of the expected product.

G) tert-Butylmethyl[4-[3-(trifluoromethyl)phenyl]piperidin-4-yl]methyl]carbamate

A mixture of 21 g of the compound obtained in the preceding step in 2 gof 10% palladium on carbon in 300 ml of MeOH is hydrogenated at AT underatmospheric pressure for 12 hours. The catalyst is filtered off and thefiltrate is concentrated under vacuum. This gives 16 g of the expectedproduct.

Preparation 1.18

4-(3-Chlorophenyl)-4-piperidinecarbonitrile hydrochloride

(IVa), HCl: R₁═3-Cl; R₂═H.

A) tert-Butyl-4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylate

A suspension of 15.8 g of sodium hydride of a concentration of 60% inoil in 400 ml of DMSO is admixed dropwise at AT under an inertatmosphere with a solution of 30 g of 3-chlorophenylacetonitrile in 200ml of THF and then with a solution of 45.5 g of tert-butylbis(2-chloroethyl)carbamate in 200 ml of DMSO and is heated at 60° C.overnight. The reaction mixture is poured into an ice/water mixture andextracted with ether, the organic phase is washed with water and driedover Na₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with DCM. This gives 33 g of theexpected product.

B) 4-(3-Chlorophenyl)-4-piperidinecarbonitrile hydrochloride

A mixture of 6.7 g of the compound obtained in the preceding step, 100ml of 2N hydrochloric ether solution and 20 ml of MeOH is left withstirring at AT for 3 hours. It is concentrated under vacuum, the residueis taken up in ether and the precipitate formed is isolated withsuction. This gives 4.65 g of the expected product, m.p.=198° C.

Preparation 1.19

4-(3-methoxyphenyl)-4-piperidinecarbonitrile hydrochloride

(IVa), HCl: R₁═3-OCH₃; R₂═H.

A) tert-Butyl 4-(3-methoxyphenyl)-4-cyanopiperidine-1-carboxylate

This compound is prepared by the procedure described in step A ofpreparation 1.8, from 16.3 g of sodium hydride at a concentration of 60%in oil in 400 ml of DMSO, 30 g of 3-methoxyphenylacetonitrile in 150 mlof THF and 47 g of tert-butyl bis(2-chloroethyl)carbamate in 100 ml ofDMSO. This gives 54 g of the expected product.

B) 4-(3-Methoxyphenyl)-4-piperidinecarbonitrile hydrochloride

A mixture of 48 g of the compound obtained in the preceding step, 300 mlof 2N hydrochloric ether solution and 50 ml of MeOH is left withstirring at AT for 2 hours. The precipitate formed is isolated withsuction to give 30.5 g of the expected product, m.p.=172° C.

Preparation 1.20

4-(Azetidin-1-ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperidine

A) 4-(Chloroformyl)-4-[3-(trifluoromethyl)phenyl]piperidinehydrochloride

A mixture of 1 g of the compound obtained in step A of preparation 1.9and 10 ml of thionyl chloride in 10 ml of DCM is heated at 60° C. for 2hours. It is concentrated under vacuum to give 1.05 g of the expectedproduct, which is used as it is.

B)4-(Azetidin-1-ylcarbonyl)-1-benzyl-4-[3-(trifluoromethyl)phenyl]piperidine

A mixture of 1.05 g of the compound obtained in the preceding step,0.283 g of azetidine and 1.15 ml of triethylamine in 10 ml of DCM isleft with stirring at AT overnight. Saturated K₂CO₃ solution is added tothe reaction mixture, which is then extracted with DCM, the extract isdried over Na₂SO₄ and the solvent is evaporated under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3;v/v) mixture. This gives 0.43 g of the expected product.

C) 4-(Azetidin-1-ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperidine

A mixture of 0.43 g of the compound obtained in the preceding step, 1 gof 10% palladium on carbon and 20 ml of MeOH is hydrogenated at 25° C.under atmospheric pressure overnight. The catalyst is filtered off andthe filtrate is concentrated under vacuum. This gives 0.33 g of theexpected product, which is used as it is.

2. Preparations of Compounds of Formula (II)

Preparation 2.1

2-Chloro-1-[4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═3-CF₃; R₂═H; R₃═H; Hal═Cl.

An ice bath is used to cool a mixture of 2.5 g of4-[3-(trifluoromethyl)phenyl]piperidine and 4 ml of triethylamine in 30ml of DCM, which is then admixed dropwise with 0.85 ml of 2-chloroacetylchloride and left with stirring for 3 hours, during which thetemperature is allowed to return to AT. It is concentrated under vacuum,the residue is taken up with aqueous 1N HCl solution and extracted withAcOEt, the organic phase is washed with saturated NaCl solution anddried over Na₂SO₄ and the solvent is evaporated under vacuum. This gives3.1 g of the expected product, which is used as it is.

Preparation 2.2

2-Chloro-1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═3-CF₃; R₂═H; R₃═—OH; Hal═Cl.

A mixture of 5 g of the compound obtained in preparation 1.1 and 10 mlof DIPEA in 40 ml of DCM is admixed dropwise and at AT with 1.63 ml of2-chloroacetyl chloride and left with stirring for 30 minutes. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v)mixture. This gives 5.5 g of the expected product, which is used as itis.

Preparation 2.3

1-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-propen-1-one

(IIb): R₁═3-CF₃; R₂═H; R₃═—OH.

An ice bath is used to cool a mixture of 5 g of the compound obtained inpreparation 1.1 and 8 ml of triethylamine in 50 ml of DCM which is thenadmixed dropwise with 2.07 ml of 3-bromopropionyl chloride and left withstirring for 2 hours, during which the temperature is allowed to returnto AT. The reaction mixture is washed with saturated K₂CO₃ solution andwith water, the organic phase is dried over Na₂SO₄ and the solvent isevaporated under vacuum. The residue is chromatographed on silica gel,eluting with a DCM/MeOH (98.5/1.5 to 97/3; v/v) mixture. This gives 4.6g of the expected product, which is used as it is.

Preparation 2.4

2-Chloro-1-[4-methoxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═3-CF₃; R₂═H; R₃═—OCH₃; Hal═Cl

A mixture of 1 g of the compound obtained in preparation 1.2 and 1.4 mlof triethylamine in 20 ml of DCM is admixed dropwise and at AT with 0.3ml of 2-chloroacetyl chloride and left with stirring at AT for 3 hours.It is concentrated under vacuum, the residue is taken up with aqueous 1NHCl solution and extracted with AcOEt, the organic phase is washed withNaCl solution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 1.2 g of the expected product, which is used as itis.

Preparation 2.5

2-Chloro-1-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═3-CF₃; R₂═H; R₃═—N(CH₃)₂; Hal═Cl.

An ice bath is used to cool a mixture of 1 g of the compound obtained inpreparation 1.3 and 1 ml of triethylamine in 20 ml of DCM which is thenadmixed dropwise with 0.35 ml of 2-chloroacetyl chloride and left withstirring, during which the temperature is allowed to return to AT. It isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with saturated K₂CO₃ solution and dried overNa₂SO₄ and the mixture is evaporated under vacuum. This gives 1.4 g ofthe expected product, which is used as it is.

Preparation 2.6

1-(2-Chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile

(IIc): R₁═3-CF₃; R₂═H; Hal═Cl.

A mixture of 4.8 g of the compound obtained in preparation 1.4, freebase, and 2.7 ml of triethylamine in 50 ml of DCM is admixed dropwiseand at AT with 1.5 ml of 2-chloroacetyl chloride and is left withstirring at AT for 1 hour. 10% HCl solution is added to the reactionmixture, which is then decanted, the organic phase is washed with 10%NaOH solution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 3.42 g of the expected product followingrecrystallization from ether; m.p.=120° C.

Preparation 2.7

tert-Butyl[1-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylcarbamate

(IIa): R₁═3-CF₃; R₂═H; R₃═—CH₂NHCOOC(CH₃)₃, Hal═Cl.

An ice bath is used to cool a mixture of 4.95 g of the compound obtainedin preparation 1.5 and 6.8 ml of triethylamine in 50 ml of DCM which isthen admixed dropwise with 1.65 ml of 2-chloroacetyl chloride and leftwith stirring, during which the temperature is allowed to return to AT.It is concentrated under vacuum, the residue is taken up with saturatedK₂CO₃ solution and extracted with AcOEt, the organic phase is washedwith saturated K₂CO₃ solution, with buffer solution pH=2 and withsaturated NaCl solution and dried over Na₂SO₄ and the mixture isevaporated under vacuum. The residue is chromatographed on silica gel,eluting with DCM/AcOEt (80/20; v/v) mixture. This gives 1.8 g of theexpected product, which is used as it is.

Preparation 2.8

1-(2-Chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide

(IIa): R₁═3-CF₃; R₂═H; R₃═—CONH₂; Hal═Cl.

A mixture of 0.7 g of the compound obtained in preparation 1.6 and 0.37ml of triethylamine in 10 ml of DCM and 10 ml of dioxane is admixeddropwise and at AT with 0.21 ml of 2-chloroacetyl chloride and is leftwith stirring at AT for 2 hours. It is concentrated under vacuum, theresidue is taken up in water, and the precipitate formed is isolatedwith suction and dried. This gives 0.82 g of the expected product,m.p.=195-198° C.

Preparation 2.9

2-Chloro-1-[4-hydroxy-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═2-CF₃; R₂═H; R₃═—OH; Hal═Cl.

An ice bath is used to cool a mixture of 1.8 g of the compound obtainedin preparation 1.7 and 1 ml of triethylamine in 20 ml of DCM which isthen admixed dropwise with 0.65 ml of 2-chloroacetyl chloride and leftwith stirring for 1 hour, during which the temperature is allowed toreturn to AT. Water is added to the reaction mixture, which isconcentrated under vacuum to remove the DCM and subjected to extractionwith AcOEt, the organic phase is washed with water and with saturatedNaCl solution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives 1.8 g of the expected product, which is used as itis.

Preparation 2.10

1-(2-Chloroacetyl)-4-[2-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile

(IIc): R₁═2-CF₃; R₂═H; Hal═Cl.

A mixture of 2.1 g of the compound obtained in preparation 1.8 and 2 mlof triethylamine in 20 ml of DCM is admixed at AT with 0.6 ml of2-chloroacetyl chloride and left with stirring for 30 minutes. It isconcentrated under vacuum, and the residue is taken up with 10% HClsolution and extracted with AcOEt, the organic phase is washed withwater, with saturated K₂CO₃ solution and with saturated NaCl solutionand dried over Na₂SO₄ and the solvent is evaporated under vacuum. Thisgives 2.3 g of the expected product.

Preparation 2.11

[1-(2-Chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methylacetate

(IIa): R₁═3-CF₃; R₂═H; R₃═—CH₂OCOCH₃; Hal═Cl.

A mixture of 1 g of the compound obtained in preparation 1.10 and 0.46ml of triethylamine in 20 ml of DCM is cooled to 0° C., 0.27 ml of2-chloroacetyl chloride is added and the mixture is left with stirringat 0° C. for 30 minutes. Water is added to the reaction mixture, whichis extracted with DCM, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. This gives 0.9 g of the expectedproduct.

Preparation 2.12

2-Chloro-1-[4-hydroxy-4-[4-(trifluoromethyl)phenyl]-1-piperidyl)-1-ethanone

(IIa): R₁═4-CF₃; R₂═H; R₃═—OH; Hal═Cl.

An ice bath is used to cool a mixture of 1.2 g of the compound obtainedin preparation 1.11 and 1.2 ml of triethylamine in 20 ml of DCM which isthen admixed dropwise with 0.38 ml of 2-chloroacetyl chloride and leftwith stirring for 1 hour, during which the temperature is allowed toreturn to AT. Water is added to the reaction mixture, which is extractedwith DCM, the organic phase is dried over Na₂SO₄ and the solvent isevaporated under vacuum. This gives 1.36 g of the expected product,which is used as it is.

Preparation 2.13

2-Chloro-1-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-ethanone

(IIa): R₁═4-Cl; R₂═H; R₃═—OH; Hal═Cl.

This compound is prepared by the procedure described in preparation2.12, from 4-(4-chlorophenyl)-4-piperidinol (available commercially) and2-chloroacetyl chloride.

Preparation 2.14

1-(2-Chloroacetyl)-4-(4-chlorophenyl)-4-piperidinecarbonitrile

(IIc): R₁═4-Cl; R₂═H; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.12 and 2-chloroacetylchloride.

Preparation 2.15

2-Chloro-1-[4-hydroxy-4-(3-methylphenyl)-1-piperidyl]-1-ethanone

(IIa): R₁═3-CH₃; R₂═H; R₃═—OH; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.13 and 2-chloroacetylchloride.

Preparation 2.16

2-Chloro-1-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidyl]-1-ethanone

(IIa): R₁═3-OCH₃; R₂═H; R₃═—OH; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.14 and 2-chloroacetylchloride.

Preparation 2.17

2-Chloro-1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidyl]-1-ethanone

(IIa): R₁═3-CF₃; R₂═4-Cl; R₃═—OH; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol and2-chloroacetyl chloride.

Preparation 2.18

N-[1-(2-Chloroacetyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidyl]-acetamide

(IIa): R₁═3-CF₃; R₂═4-Cl; R₃═—NHCOCH₃; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.2,from the compound obtained in preparation 1.15 and 2-chloroacetylchloride.

Preparation 2.19

2-Chloro-1-[4-hydroxy-4-[3-(trifluoromethoxy)phenyl]-1-piperidyl]-1-ethanone

(IIa): R₁═3-OCF₃; R₂═H; R₃═—OH; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.16 and 2-chloroacetylchloride.

Preparation 2.20

tert-Butyl[[1-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]-methylcarbamate

(IIa): R₁═3-CF₃; R₂═H; R₃═—CH₂N(CH₃)COOC(CH₃)₃; Hal═Cl.

A solution of 14 g of the compound obtained in preparation 1.17 and 5.5ml of triethylamine in 300 ml of DCM is cooled to −40° C., 3.1 ml of2-chloroacetyl chloride are added slowly and the mixture is left withstirring, during which the temperature is allowed to return to AT. It isconcentrated under vacuum, the residue is taken up in water andextracted with AcOEt, the organic phase is washed with buffer pH=2 andwater and dried over Na₂SO₄ and the solvent is evaporated under vacuum.This gives 15.33 g of the expected product.

Preparation 2.21

1-(2-Chloroacetyl)-4-(3-chlorophenyl)-4-piperidinecarbonitrile

(IIc): R₁═3-Cl; R₂═H; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.18 and 2-chloroacetylchloride.

Preparation 2.22

1-(2-Chloroacetyl)-4-(3-methoxyphenyl)-4-piperidinecarbonitrile

(IIc): R₁═3-OCH₃; R₂═H; Hal═Cl.

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.19 and 2-chloroacetylchloride.

Preparation 2.23

4-(Azetidin-1-ylcarbonyl)-1-(2-chloroacetyl)-4-[3-(trifluoromethyl)phenyl]-piperidine

This compound is prepared by the procedure described in preparation 2.1,from the compound obtained in preparation 1.20 and 2-chloroacetylchloride.

3. Preparations of Compounds of Formula (III).

Preparation 3.1

1-(2-Pyrazinyl)piperazine

(III) pp=1;

A mixture of 3 g of piperazine, 1.04 ml of 2-chloropyrazine and 1.85 gof K₂CO₃ in 100 ml of EtOH is heated at reflux for 48 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upin water, the system is rendered alkaline to pH=10 by addition of 10%NaOH and subjected to extraction with chloroform, the organic phase iswashed with water and dried over Na₂SO₄ and the solvent is evaporatedunder vacuum. This gives 1.8 g of the expected product followingrecrystallization from hexane.

Preparation 3.2

1-(3-Pyridyl)piperazine

(III): p=1;

This compound is prepared by the procedure described in TetrahedronLetters, 1998, 39, 617-620.

Preparation 3.3

3-(1-piperazinyl)pyridazine trihydrochloride

(III), 3HCl: p=1;

A) tert-Butyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate

A mixture of 13.52 g of tert-butyl 1-piperazinecarboxylate, 10.81 g of3,6-dichloropyridazine and 20 ml of triethylamine in 100 ml of n-butanolis heated at reflux for 5 hours. It is concentrated under vacuum and theresidue is chromatographed on silica gel, eluting with a DCM/AcOEt(90/10; v/v) mixture. This gives 14 g of the expected product, which isused as it is.

B) tert-Butyl 4-(3-pyridazinyl)-1-piperazinecarboxylate

A mixture of 10.5 g of the compound obtained in the preceding step and2.5 g of 10% palladium on carbon in 30 ml of DMF and 250 ml of EtOH ishydrogenated at AT under atmospheric pressure overnight. The catalyst isfiltered off and the filtrate is concentrated under vacuum. The residueis chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to90/10; v/v) mixture. This gives 9.1 g of the expected product, which isused as it is.

C) 3-(1-piperazinyl)pyridazine trihydrochloride

A mixture of 3.8 g of the compound obtained in the preceding step, 50 mlof a 2N solution of HCl in ether and 20 ml of MeOH is left with stirringat AT overnight. It is concentrated under vacuum, the residue is takenup in ether and the precipitate formed is isolated with suction. Thisgives 3 g of the expected product, which is used as it is.

Preparation 3.4

3-Chloro-6-(1-piperazinyl)pyridazine trihydrochloride

(III), 3HCl: p=1;

A mixture of 2.96 g of the compound obtained in step A of preparation3.3 and 30 ml of a 6N solution of HCl in MeOH is left with stirring inAT overnight. The reaction mixture is concentrated under vacuum, theresidue is taken up in DCM a number of times and each time the solventis evaporated under vacuum. This gives 2.6 g of the expected product,which is used as it is.

Preparation 3.5

4-(1-piperazinyl)pyrimidine dihydrochloride

(III), 2HCl: p=1;

A) tert-Butyl 4-(2-chloro-4-pyrimidinyl)-1-piperazinecarboxylate

A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of2,4-dichloropyrimidine and 8.6 g of NaHCO₃ in 50 ml of EtOH is heated atreflux for 1 hour. It is concentrated under vacuum, the residue is takenup in water and extracted with DCM, the organic phase is dried overNa₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40;v/v) mixture. Two compounds are separated:

-   -   the less polar compound, corresponding to tert-butyl        4-(4-chloro-2-pyrimidinyl)-1-piperazinecarboxylate, of which        1.75 g are obtained;    -   the more polar compound, corresponding to the compound of step        A), of which 12.9 g are obtained, and which is used as it is.

B) tert-Butyl 4-(4-pyrimidinyl)-1-piperazinecarboxylate hydrochloride

A mixture of 12.9 g of the compound obtained in the preceding step and3.2 g of 10% palladium on carbon in 300 ml of MeOH and 100 ml of DMF ishydrogenated at AT under atmospheric pressure for 2 hours. The catalystis filtered off and the filtrate is concentrated under vacuum. Thisgives 13 g of the expected product, which is used as it is.

C) 4-(1-piperazinyl)pyrimidine dihydrochloride

A mixture of 4 g of the compound obtained in the preceding step, 50 mlof a 2N solution of HCl in ether and 30 ml of MeOH is left with stirringat AT for 2 hours. The precipitate formed is isolated with suction andwashed with ether. This gives 3 g of the expected product, which is usedas it is.

Preparation 3.6

5-(1-piperazinyl)pyrimidine×hydrochloride

(III), ×HCl: p=1;

A) tert-Butyl 4-(5-pyrimidinyl)-1-piperazinecarboxylate

Argon is bubbled for 15 minutes into a mixture of 9.3 g of tert-butyl1-piperazinecarboxylate, 7.95 g of 5-bromopyrimidine and 6.5 g of sodiumtert-butoxide in 250 ml of toluene, which is then heated at reflux,0.277 g of palladium acetate and 1.7 ml of tri-tert-butylphosphine areadded and reflux is continued for 24 hours. 0.277 g of palladium acetateis added and the mixture is heated at reflux for 8 hours. The reactionmixture is cooled to AT, water is added, the mixture is subjected toextraction with AcOEt, the organic phase is filtered and dried overNa₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with DCM, then with a DCM/AcOEt(50/50; v/v) mixture and finally with a DCM/MeOH (95/5; v/v) mixture.This gives 3.95 g of the expected product following recrystallizationfrom a DCM/hexane/iso ether mixture.

B) 5-(1-piperazinyl)pyrimidine×hydrochloride

A mixture of 3.5 g of the compound obtained in the preceding step in 20ml of dioxane is admixed at AT with 50 ml of a 2N solution of HCl inether, which is left with stirring at AT for 1 hour and concentratedunder vacuum. This gives a yellow solid which is used as it is.

Preparation 3.7

4-(1-piperazinyl)pyridazine

(III): p=1;

A) 5-(4-Benzyl-1-piperazinyl)-4-chloro-3(2H)-pyridazinone

A mixture of 7 g of 1-benzylpiperazine, 6.55 g of4,5-dichloro-3(2H)-pyridazinone and 11 g of K₂CO₃ in 150 ml of DMF isheated at 110° C. for 4 hours and then concentrated under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5;v/v) mixture. The product obtained is taken up in iso ether andtriturated and the precipitate formed is isolated with suction. Thisgives 7 g of the expected product, which is recrystallized from isoether; m.p.=173-175° C.

B) 5-(4-Benzyl-1-piperazinyl)-3,4-dichloropyridazine

A mixture of 1.7 g of the compound obtained in the preceding step and 20ml of phosphorus oxychloride is heated at 85° C. for 4 hours. Aftercooling to AT the reaction mixture is poured onto ice, the aqueous phaseis rendered alkaline by addition of concentrated NaOH solution andextracted with DCM, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel, eluting with a DCM/MeOH (97/3 to 90/10; v/v) mixture. Thisgives 1.5 g of the expected product, which is used as it is.

C) 4-(1-piperazinyl)pyridazine

A mixture of 1.3 g of the compound obtained in the preceding step and0.13 g of 10% palladium on carbon in 20 ml of MeOH is hydrogenated at30° C. under atmospheric pressure for 3 hours. The catalyst is filteredoff and the filtrate is concentrated under vacuum. This gives 0.85 g ofthe expected product, which is used as it is.

Preparation 3.8

5-(1-piperazinyl)-3(2H)-pyridazinone hydrochloride

(III), HCl: p=1;

A mixture of 0.8 g of the compound obtained in step A of preparation 3.8and 0.3 g of 10% palladium on carbon in 30 ml of MeOH is hydrogenated at30° C. under atmospheric pressure for 2 hours. The catalyst is filteredand the filtrate is concentrated under vacuum. This gives 0.38 g of theexpected product, which is used as it is.

Preparation 3.9

4-(1-piperazinyl)-3(2H)-pyridazinone hydrochloride

(III), HCl: p=1;

A) 4-(4-Benzyl-1-piperazinyl)-5-chloro-3(2H)-pyridazinone and5-(4-benzyl-1-piperazinyl)-4-chloro-3(2H)-pyridazinone

A mixture of 2.77 g of 1-benzylpiperazine, 1.3 g of NaHCO₃ and 2.6 g of4,5-dichloro-3(2H)-pyridazinone in 300 ml of dioxane is heated at 100°C. overnight and then concentrated under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH (98/2; v/v)mixture. Two compounds are separated:

-   -   the less polar compound,        4-(4-benzyl-1-piperazinyl)-5-chloro-3(2H)-pyridazinone, of which        0.8 g is obtained;    -   the more polar compound,        5-(4-benzyl-1-piperazinyl)-4-chloro-3(2H)-pyridazinone, of which        1.2 g are obtained.

B) 4-(1-piperazinyl)-3(2H)-pyridazinone hydrochloride

A mixture of 0.75 g of the less polar compound obtained in the precedingstep and 0.2 g of 10% palladium on carbon in 20 ml of MeOH and 10 ml ofDMF is hydrogenated at 30° C. under atmospheric pressure for 3 hours.The catalyst is filtered off and the filtrate is concentrated undervacuum. This gives 0.46 g of the expected product, which is used as itis.

Preparation 3.10

1-(2-Pyrimidinyl)-1,4-diazepane

(III): p=2;

An ice bath is used to cool a solution of 3 g of 2-chloropyrimidine in20 ml of EtOH which is then admixed dropwise with a solution of 13 g of1,4-diazepane in 50 ml of EtOH, left with stirring in the cold for 30minutes and then at AT for 24 hours. It is concentrated under vacuum,the residue is taken up with 100 ml of AcOEt and 100 ml of saturatedK₂CO₃ solution, the system is decanted, the organic phase is diluted byadding 100 ml of AcOEt, the organic phase is washed with saturated K₂CO₃solution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. This gives the expected product, which is used as it is.

Preparation 3.11

2-Chloro-6-(1-piperazinyl)pyrazine hydrochloride

(III), HCl: p=1;

A) tert-Butyl 4-(6-chloropyrazin-2-yl)-1-piperazinecarboxylate

A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4 g of2,6-dichloropyrazine and 9.5 ml de DIPEA in 40 ml of n-butanol is heatedat reflux for 3 hours. It is concentrated under vacuum, the residue istaken up in 100 ml of EtOH, the system is left to stand overnight andthe crystalline product formed is isolated with suction. This gives 4.7g of the expected product, m.p.=108° C.

B) 2-Chloro-6-(1-piperazinyl)pyrazine hydrochloride

A mixture of 1.5 g of the compound obtained in the preceding step and100 ml of 2N hydrochloric ether solution in 10 ml of MeOH is left withstirring at AT overnight. The precipitate formed is isolated withsuction and washed with ether. This gives 1.2 g of the expected product.

Preparation 3.12

4-Chloro-2-(1-piperazinyl)pyrimidine×hydrochloride

(III), ×HCl: p=1;

A) tert-Butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate andtert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate

A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of2,4-dichloropyrimidine and 8.6 g of NaHCO₃ in 90 ml of EtOH is heated at100° C. for one hour. It is concentrated under vacuum, the residue istaken up in water and extracted with DCM, the organic phase is driedover Na₂SO₄ and the solvent is evaporated under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40;v/v) mixture. Two compounds are separated:

-   -   the less polar compound, tert-butyl        4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate, of which        1.75 g are obtained;    -   the more polar compound, tert-butyl        4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate, of which        12.9 g are obtained.

B) 4-Chloro-2-(1-piperazinyl)pyrimidine×hydrochloride

A mixture of 1.75 g of the less polar compound obtained in the precedingstep and 100 ml of 2N hydrochloric ether solution in 10 ml of MeOH isleft with stirring at AT for 18 hours. It is concentrated under vacuum,the residue is taken up in ether and the crystalline product formed isisolated with suction. This gives 1.6 g of the expected product.

Preparation 3.13

6-Chloro-4-(1-piperazinyl)pyrimidine hydrochloride

(III), HCl: p=1;

A solution of 14.8 g of 4,6-dichloropyrimidine in 100 ml of acetonitrileis cooled to 0-5° C., a solution of 20 g of anhydrous piperazine in 200ml of acetonitrile is added over 30 minutes and the mixture is left withstirring at 0-5° C. for 2 hours. It is concentrated under vacuum, theresidue is taken up with 100 ml of 2N NaOH and extracted with ether, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. The hydrochloride is formed, giving 15 g of the expectedproduct.

EXAMPLE 1 Compound No. 12-[4-(2-Pyrazinyl)-1-piperazinyl]-1-[4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-1-ethanonehydrochloride, 2H₂O

(I), HCl: R₁═3-CF₃; R₂═H; R₃═H;

n=1; p=1.

A mixture of 0.7 g of the compound obtained in preparation 2.1, 0.39 gof the compound obtained in preparation 3.1, 0.39 g of potassium iodideand 0.635 g of K₂CO₃ in 30 ml of acetonitrile is left with stirring atAT overnight. Water is added to the reaction mixture, which is extractedwith AcOEt, the organic phase is washed with water and with saturatedNaCl solution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH (97/3; v/v) mixture. The product obtained is taken up in 2Nhydrochloric ether solution and, after trituration, the precipitateformed is isolated with suction. This gives 0.42 g of the expectedproduct.

Mass spectrum: MH⁺=434.3.

EXAMPLE 2 Compound No. 21-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-[5-trifluoromethyl)-2-pyridyl]-1-piperazinyl]-1-ethanonedioxalate

(I), 2C₂H₂O₄: R₁═3-CF₃; R₂═H; R₃═—OH;

n=1; p=1.

A mixture of 0.8 g of the compound obtained in preparation 2.2, 0.575 gof 1-[5-(trifluoromethyl)-2-pyridyl]piperazine, 0.413 g of potassiumiodide and 0.688 g of K₂CO₃ in 20 ml of acetonitrile is left withstirring at AT for 2 hours. Saturated K₂CO₃ solution is added, themixture is extracted with AcOEt, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄ and the solventis evaporated under vacuum. The residue is chromatographed on silicagel, eluting the DCM/MeOH (96/4; v/v) mixture. The product obtained istaken up in ether, 0.384 g of oxalic acid is added, the system istriturated and the precipitate formed is isolated with suction. Thisgives 1.27 g of the expected product, m.p.=173° C.

EXAMPLE 3 Compound No. 31-[4-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-3-[4-(2-pyrazinyl]-1-piperazinyl]-1-propanone1.5 oxalate, 1.5H₂O

(I), 1.5 C₂H₂O₄: R₁═3-CF₃; R₂═H; R₃═—OH;

n=2; p=4.

A mixture of 0.5 g of the compound obtained in preparation 2.3, 0.660 gof the compound obtained in preparation 3.1, 0.4 ml of triethylamine and0.23 g of potassium iodide in 10 ml of acetonitrile is heated at 70° C.for 60 hours. Water is added to the reaction mixture, which is extractedwith AcOEt, the organic phase is washed with saturated K₂CO₃ solution,with water and with saturated NaCl solution and dried over Na₂SO₄ andthe solvent is evaporated under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH (94/6; v/v) mixture. 0.77 g ofthe product obtained is taken up in ether, 0.28 g of oxalic acid isadded, and the precipitate formed is isolated with suction. This gives0.762 g of the expected product, m.p.=113° C.

EXAMPLE 4 Compound No. 41-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-CF₃; R₂═H; R₃═—CH₂NH₂;

n=1; p=1.

A)1-[2-[4-(2-Pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile

A mixture of 3.42 g of the compound obtained in preparation 2.6, 1.7 gof the compound obtained in preparation 3.1, 1.7 g of potassium iodideand 1.42 g of K₂CO₃ in 50 ml of acetonitrile is left with stirring at ATfor 18 hours. The mixture is concentrated under vacuum, the residue istaken up in water and extracted with AcOEt, the organic phase is driedover Na₂SO₄ and the solvent is evaporated under vacuum. The residue istaken up in absolute EtOH, and the crystals formed are isolated withsuction and washed with ether. This gives 3.5 g of the expected product,m.p.=138° C.

B)1-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

A mixture of 3 g of the compound obtained in the preceding step, 0.3 gof Raney® nickel, 20 ml of 20% aqueous ammonia and 200 ml of MeOH ishydrogenated at AT under atmospheric pressure for 16 hours. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with AcOEt, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated under vacuum. Thisgives 2.17 g of the expected product following recrystallization fromAcOEt; m.p.=155° C.

Mass spectrum: MH⁺=463.4.

¹H NMR: DMSO-d6: δ (ppm): 1.0 to 1.2: m: 2H, 1.6 to 2.2: m: 4H, 2.4 to4.0: m: 16H, 7.4 to 7.7: m: 4H, 7.79: d: 1H, 8.06: dd: 1H, 8.29: d: 1H.

Compound No. 4 of Example 4 can also be obtained by following the twosteps below:

A′) tert-Butyl[1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)-phenyl]-4-piperidyl]methylcarbamate

A mixture of 2.8 g of the compound obtained in preparation 2.7, 1.25 gof the compound obtained in preparation 3.1, 1.1 g of potassium iodideand 1.8 g of K₂CO₃ in 30 ml of acetonitrile is left with stirring at ATfor 3 hours. Saturated K₂CO₃ solution is added, the mixture is extractedwith AcOEt, the organic phase is dried over Na₂SO₄ and the solvent isevaporated under vacuum. The residue is chromatographed on silica gel,eluting with a DCM/MeOH (97/3: v/v) mixture. This gives 1.75 g of theexpected product.

B′)1-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

A mixture of 1.7 g of the compound obtained in the preceding step, 50 mlof a 2N solution of HCl in ether and 30 ml of MeOH is left with stirringat AT for 4 hours. It is concentrated under vacuum, the residue is takenin water, the aqueous phase is washed with AcOEt, the aqueous phase isrendered alkaline by addition of K₂CO₃, the mixture is subjected toextraction with AcOEt, the organic phase is washed with saturated NaClsolution and dried over Na₂SO₄ and the solvent is evaporated undervacuum. The product crystallizes on evaporation in AcOEt and thecrystals formed are isolated with suction. This gives 1.05 g of theexpected product, m.p.=152-153° C.

Mass spectrum: MH⁺=463.3.

EXAMPLE 5 Compound No. 51-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]-1-ethanonetrihydrochloride

(I), 3HCl: R₁═3-CF₃; R₂═H; R₃═—CH₂NH₂;

n=1; p=1.

A)1-[2-[4-(2-Pyrimidinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile

A mixture of 1.28 g of the compound obtained in preparation 2.6, 1.1 gof 2-(1-piperazinyl)pyrimidine, 1.23 g of K₂CO₃ and 0.79 g of potassiumiodide in 30 ml of acetonitrile is left with stirring at AT for 4 hours.It is concentrated under vacuum, the residue is taken up in water andextracted with DCM, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel H, eluting with a DCM/MeOH (100/1; v/v) mixture. This gives0.9 g of the expected product.

B)1-[4-(Aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrimidinyl)-1-piperazinyl]-1-ethanonetrihydrochloride

A mixture of 0.9 g of the compound obtained in the preceding step, 0.1 gof Raney® nickel, 10 ml of 20% aqueous ammonia and 50 ml of MeOH ishydrogenated at AT under atmospheric pressure for 4 hours. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with DCM, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated under vacuum. Theresidue is taken up in a 2N solution of HCl in ether and the precipitateformed is isolated with suction. This gives 0.74 g of the expectedproduct after drying under vacuum; m.p.=198-202° C.

EXAMPLE 6 Compound No. 272-[4-(4-Pyrimidinyl)-1-piperazinyl]-1-[4-[3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-1-ethanonedioxalate

A mixture of 0.87 g of Compound No. 11, 5 ml of 35% HCl solution and 9ml of acetic acid is heated at 110° C. for 1 hour. After cooling to AT,5% K₂CO₃ solution is added, the mixture is extracted with AcOEt, theorganic phase is washed with saturated NaCl and dried over Na₂SO₄ andthe solvent is evaporated under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. 0.7 g of theproduct obtained is taken up in MeOH, 0.12 g of oxalic acid is added,the system is left in crystallization and the precipitate formed isisolated with suction. This gives 0.502 g of the expected product,m.p.=160° C.

Mass spectrum: MH⁺=432.3.

EXAMPLE 7 Compound No. 301-[4-(Aminomethyl)-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone1.5 oxalate, 0.5 H₂O

(I), 1.5 C₂H₂O₄: R₁═2-CF₃; R₂═H; R₃═—CH₂NH₂;

n=1; p=1.

A)1-[2-[4-(2-Pyrazinyl)-1-piperazinyl]acetyl]-4-[2-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile1.5 oxalate

A mixture of 1 g of the compound obtained in preparation 2.10, 0.496 gof the compound obtained in preparation 3.1, 0.51 g of potassium iodideand 0.836 g of K₂CO₃ in 20 ml of acetonitrile is left with stirring atAT overnight. It is concentrated under vacuum, the residue is taken upin water and extracted with AcOEt, the organic phase is washed withwater and with saturated NaCl solution and dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. 0.29 g of theproduct obtained is taken up in MeOH, 0.057 g of oxalic acid is addedand the precipitate formed is isolated with suction. This gives 0.081 gof the expected product, m.p.=125-126° C.

B)1-[4-(Aminomethyl)-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone1.5 oxalate, 0.5 H₂O

A mixture of 0.8 g of the compound obtained in the preceding step, 0.08g of Raney® nickel, 20 ml of 20% aqueous ammonia and 100 ml of MeOH ishydrogenated at AT under atmospheric pressure for 36 hours. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with AcOEt, the organic phaseis washed with saturated NaCl solution and dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The product is chromatographed onsilica gel, eluting with a DCM/MeOH (90/10; v/v) mixture. 0.28 g of theproduct obtained is taken up in AcOEt, 0.054 g of oxalic acid is addedand the precipitate formed is isolated with suction. This gives 0.26 gof the expected product.

Mass spectrum: MH⁺=463.4.

EXAMPLE 8 Compound No. 321-[4-(Hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-CF₃; R₂═H; R₃═—CH₂OH;

n=1; p=1.

A mixture of 0.6 g of Compound No. 31 and 0.14 g of KOH pellets in 10 mlof MeOH and 5 ml of water is heated at 70° C. for 10 minutes. Aftercooling to AT, the crystalline product formed is isolated with suction,washed with water and dried. This gives 0.3 g of the expected product,m.p.=223° C.

Mass spectrum: MH⁺=464.4.

EXAMPLE 9 Compound No. 331-[4-[(Dimethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-CF₃; R₂═H; R₃═—CH₂N(CH₃)₂;

n=1; p=1.

A mixture of 0.85 g of Compound No. 4 obtained in Example 4, 0.28 ml of37% aqueous formaldehyde solution, 3.8 g of sodium triacetoxyborohydrideand 3 drops of acetic acid in 50 ml of THF is left with stirring at ATovernight. The reaction mixture is concentrated under vacuum, theresidue is taken up in 100 ml of water and the system is heated at 80°C. for 30 minutes. After cooling to AT, the reaction mixture is renderedalkaline to pH=9 by addition of 10% NaOH solution and extracted withDCM. The organic phase is dried over Na₂SO₄ and the solvent isevaporated under vacuum. This gives 0.55 g of the expected productfollowing recrystallization from ether; m.p.=118° C.

Mass spectrum: MH⁺=491.4.

¹H NMR: DMSO-d₆: δ (ppm): 1.6-2.3: m: 10H, 2.35-2.7: m: 6H, 2.8-3.3: m:4H, 3.4-4.0: m: 6H, 7.4-8.4: m: 7H.

EXAMPLE 10 Compound No. 361-[4-(4-Chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

A mixture of 0.907 g of Compound No. 35 and 0.913 g ofp-toluenesulphonic acid in 20 ml of toluene is heated at 118° C. for 24hours. After cooling to AT, 5% K₂CO₃ solution is added, the system isextracted with AcOEt, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 0.55g of the expected product following recrystallization from a DCM/isoether mixture; m.p.=139-141° C.

EXAMPLE 11 Compound No. 371-[4-(Aminomethyl)-4-(4-chlorophenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonetrifluoroacetate

(I), TFA: R₁═4-Cl; R₂═H; R₃═—CH₂NH₂;

n=1; p=1.

A)4-(4-Chlorophenyl)-1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-piperidinecarbonitrile

A mixture of 1 g of the compound obtained in preparation 2.14, 0.56 g ofthe compound obtained in preparation 3.1, 0.56 g of potassium iodide and0.47 g of K₂CO₃ in 20 ml of acetonitrile is left with stirring at ATovernight. It is concentrated under vacuum, the residue is taken up inwater and extracted with AcOEt, the organic phase is dried over Na₂SO₄and the solvent is evaporated under vacuum. This gives 1.51 g of theexpected product, which is used as it is.

B)1-[4-(Aminomethyl)-4-phenyl-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonetrifluoroacetate and1-[4-(aminomethyl)-4-(4-chlorophenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonetrifluoroacetate

A mixture of 1.51 g of the compound obtained in the preceding step, and0.15 g of rhodium on alumina in 100 ml of MeOH is hydrogenated at ATunder atmospheric pressure for 36 hours. The catalyst is filtered offand the filtrate is concentrated under vacuum. The residue ischromatographed on silica gel H, eluting with a DCM/MeOH (100/5; v/v)mixture and then with a DCM/MeOH/H₂O (100/5/0.5; v/v/v) mixture. Theproduct obtained is taken up, in the form of a mixture of two compounds,in EtOH, 2N hydrochloric ether solution is added and the precipitateformed is isolated with suction. The precipitate is dissolved in water,the aqueous phase is washed with DCM, the aqueous phase is renderedalkaline by addition of 10% NaOH solution and extracted with DCM, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. The residue is recrystallized from AcOEt to give 0.14 g of themixture of the two compounds, containing 21.6% of one compound and 75.5%of Compound No. 37. Preparative HPLC is used to separate the twocompounds. A Delta Prep 4000 preparative HPLC apparatus with a PROCHROMcolumn with dynamic axial compression, with a diameter of 50 mm, and 380g of Kromasil® C18 stationary phase, compressed under a pressure of 70bars, are used. The mobile phase is a gradient of the mixture of aneluent A (H₂O+TFA 0.1%) and of an eluent B (acetonitrile/H₂O(90%+10%)+TFA 0.1%) and the flow rate is 122 ml/min. UV detection iscarried out at a wavelength of 254 nm. After 0.122 g of the mixture hasbeen separated, the product is:

-   -   0.037 g of a compound identified as being        1-[4-(aminomethyl)-4-phenyl-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone        trifluoroacetate: RT=13 min;

Mass spectrum MH⁺=395.4.

-   -   0.15 g of Compound No. 37: RT=15.9 min;

Mass spectrum MH⁺=429.4.

EXAMPLE 12 Compound No. 571-[4-[(Methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-CF₃; R₂═H; R₃═—CH₂NHCH₃;

n=1; p=1.

A) tert-Butylmethyl[[1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidyl]methyl]carbamate

A mixture of 10 g of the compound obtained in preparation 2.20, 3.7 g ofthe compound obtained in preparation 3.1, 3.7 g of potassium iodide and6.2 g K₂CO₃ in 200 ml of acetonitrile is left with stirring at AT for 5hours. It is concentrated under vacuum, the residue is taken up in waterand extracted with AcOEt, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica gel H, eluting with DCM and then with a DCM/MeOH (100/2; v/v)mixture. This gives 10.7 g of the expected product.

B)1-[4-[(Methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

A solution of 8 g of the compound obtained in the preceding step in 100ml of MeOH is admixed with 300 ml of 2N hydrochloric ether solution andleft with stirring at AT overnight. It is concentrated under vacuum, theresidue is taken up with 10% NaOH solution and extracted with AcOEt, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. The residue is chromatographed on silica gel H, eluting with aDCM/MeOH (100/2; v/v) mixture and then with a DCM/MeOH/water (100/5/0.5;v/v/v) mixture. This gives 4.5 g of the expected product followingrecrystallization from iso ether; m.p.=137-139° C.

Mass spectrum MH⁺=477.4.

¹H NMR: DMSO-d₆: δ (ppm): 1.10: s: 1H, 1.6-2.3: m: 7H, 2.4-3.8: m: 16H,7.4-7.75: m: 4H, 7.8: d: 1H, 8.15: dd: 1H, 8.3: d: 1H.

EXAMPLE 13 Compound No. 581-[4-(Isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-CF₃; R₂═H; R₃═—CH₂NHCH(CH₃)₂;

n=1; p=1.

A mixture of 1 g of Compound No. 4, 0.16 ml of acetone and 5 drops ofacetic acid in 10 ml of THF is admixed at AT with 0.5 g of sodiumtriacetoxyborohydride and is left with stirring at AT overnight.Subsequently 20 ml of MeOH are added and the mixture is heated at 55° C.for 1 hour. It is concentrated under vacuum, the residue is taken upwith 30% NaOH solution and extracted with DCM, the organic phase isdried over Na₂SO₄ and the solvent is evaporated under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOH (93/7;v/v) mixture. This gives 0.511 g of the expected product followingrecrystallization from ether; m.p.=═140-141° C.

Mass spectrum: MH⁺═505.3.

EXAMPLE 14 Compound No. 591-[4-[(N-methylisopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonetrihydrochloride

(I), 3HCl: R₁═3-CF₃; R₂═H; R₃═—CH₂N(CH₃)CH(CH₃)₂;

n═1; p═1.

A mixture of 0.36 g of Compound No. 58, 0.08 ml of 37% aqueousformaldehyde solution and 5 drops of acetic acid in 10 ml of THF isadmixed at AT with 0.605 g of sodium triacetoxyborohydride and is leftwith stirring at AT for 4 hours. Subsequently 10 ml of MeOH are addedand the mixture is heated at 60° C. for 1 hour. It is concentrated undervacuum, the residue is taken up with 30% NaOH solution and extractedwith DCM, the extract is dried over Na₂SO₄ and the solvent is evaporatedunder vacuum. The residue is chromatographed using a DCM/MeOH (96/4;v/v) mixture. The product obtained is taken up in 2N hydrochloric ethersolution and the precipitate formed is isolated with suction. This gives0.233 g of the expected product, m.p.=185-200° C.

Mass spectrum: MH⁺═519.3.

EXAMPLE 15 Compound No. 651-[4-(Aminomethyl)-4-(3-chlorophenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

(I): R₁═3-Cl; R₂═H; R₃═—CH₂NH₂;

n═1; p═1.

A)4-(3-Chlorophenyl)-1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-piperidinecarbonitrile

A mixture of 2.3 g of the compound obtained in preparation 2.21, 1.3 gof the compound obtained in preparation 3.1, 1.3 g of potassium iodideand 2.2 g of K₂CO₃ in 40 ml of acetonitrile is left with stirring at ATovernight. Water is added to the reaction mixture, which is extractedwith AcOEt, the organic phase is washed with saturated K₂CO₃ solutionand with water and dried over Na₂SO₄ and the solvent is evaporated undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH (97/3; v/v) mixture. This gives 2.3 g of the expected product.

B)1-[4-(Aminomethyl)-4-(3-chlorophenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone

A mixture of 0.62 g of the compound obtained in the preceding step and0.6 g of Raney® nickel in 30 ml of MeOH is hydrogenated at 28° C. underatmospheric pressure for 8 hours. The catalyst is filtered off and thefiltrate is concentrated under vacuum. The residue is chromatographedunder alumina, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives0.121 g of the expected product following recrystallization from theDCM/iso ether mixture; m.p.=138-139° C.

Mass spectrum: MH⁺═429.3.

EXAMPLE 16 Compound No. 691-[4-(Aminomethyl)-4-(3-methoxyphenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonedioxalate

(I), 2C₂H₂O₄: R₁═3-OCH₃; R₂═H; R₃═—CH₂NH₂;

n═1; p═1.

A)4-(3-Methoxyphenyl)-1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-piperidinecarbonitrile

A mixture of 1.2 g of the compound obtained in preparation 2.22, 0.675 gof the compound obtained in preparation 3.1, 0.68 g of potassium iodideand 1.2 g of K₂CO₃ in 30 ml of acetonitrile is left with stirring at ATfor 4 hours. Water is added, the mixture is extracted with DCM, theorganic phase is washed with saturated K₂CO₃ solution and water anddried over Na₂SO₄ and the solvent is evaporated under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOH (97/3;v/v) mixture. This gives 1.5 g of the expected product, of which aportion is recrystallized from iso ether; m.p.=108° C.

B)1-[4-(Aminomethyl)-4-(3-methoxyphenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanonedioxalate

A mixture of 1.3 g of the compound obtained in the preceding step, 0.2 gof Raney® nickel and 10 ml of concentrated aqueous ammonia solution in70 ml of MeOH is hydrogenated at 31° C. under atmospheric pressure for30 hours. The catalyst is filtered off and the filtrate is evaporatedunder vacuum. The residue is taken up in 1N HCl solution, the aqueousphase is washed with AcOEt, the aqueous phase is rendered alkaline byaddition of 10% NaOH solution, the mixture is extracted with DCM, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated undervacuum. 0.2 g of the product obtained is taken up in ether, 0.042 g ofoxalic acid is added and the precipitate formed, following trituration,is isolated with suction. This gives 0.19 g of the expected product,m.p.=120° C.

Mass spectrum: MH⁺═425.4.

The table below illustrates the chemical structures and physicalproperties of some examples of compounds according to the invention.

In this table

-   -   the value R₃═double bond indicates that R₃, together with the        adjacent carbon atom of the piperidine ring, forms a double        bond, as illustrated in Example 6;    -   Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, n-Pe and i-Pe represent,        respectively, the groups methyl, ethyl, n-propyl, isopropyl,        n-butyl, isobutyl, n-pentyl and isopentyl.

TABLE I (I)

M.p. ° C.; salt recrystallization Compound solvent; No. n p R₁ R₂ R₃ R₄MH⁺  1 1 1 3-CF₃ H H

HCIether434.3  2 1 1 3-CF₃ H —OH

173; dioxalateether—  3 2 1 3-CF₃ H —OH

113; 1.5 oxalateether—  4 1 1 3-CF₃ H —CH₂NH₂

155AcOEt463.4  5 1 1 3-CF₃ H —CH₂NH₂

198-202; 3 HClether—  6(a) 1 1 3-CF₃ H —OH

145-146DCM/iso ether—  7(b) 1 1 3-CF₃ H —OH

105; oxalateether—  8(b) 1 1 3-CF₃ H —OH

144 (dec.):trioxalateether—  9(b) 1 1 3-CF₃ H —OH

102; dioxalateether— 10(a) 1 1 3-CF₃ H —OH

99DCM/iso ether— 11(b) 1 1 3-CF₃ H —OH

2.5 oxalateether450.3 (base) 12(a) 1 1 3-CF₃ H —OH

126DCM/iso ether— 13(a) 1 1 3-CF₃ H —OH

133-134DCM/iso ether— 14(a) 1 1 3-CF₃ H —OH

137DCM/iso ether— 15(a) 1 1 3-CF₃ H —OH

128-130DCM/iso ether— 16 1 1 3-CF₃ H —OH

TFA—450.4 17(a) 1 1 3-CF₃ H —OH

140-200iso ether— 18(a) 1 1 3-CF₃ H —OH

189-191DCM/iso ether— 19(a) 1 2 3-CF₃ H —OH

135DCM/iso ether— 20(b) 1 2 3-CF₃ H —OH

98-102; oxalateether/pentane— 21 1 2 3-CF₃ H —OH

147-149DCM/iso ether— 22(c) 2 2 3-CF₃ H —OH

125-126; 2HClether545.4 23(d) 1 1 3-CF₃ H —OMe

92-104; 3HClether— 24(e) 1 1 3-CF₃ H —NMe₂

2 oxalateether/MeOH477.5 25(f) 1 1 3-CF₃ H —CONH₂

178-185; 3HClether477.5 26(g) 1 1 2-CF3 H —OH

218iso ether— 27(h) 1 1 3-CF₃ H Double bond

160; dioxalateMeOH432.3 28(i) 1 1 3-CF₃ H Double bond

164; oxalateMeOH432.4 29(j) 1 1 2-CF3 H Double bond

196; oxalateMeOH432.4 30 1 1 2-CF3 H —CH₂NH₂

1.5 oxalateAcOEt463.4 31(k) 1 1 3-CF₃ H —CH₂OCOMe

2 HClether506.4 32 1 1 3-CF₃ H —CH₂OH

223water464.4 33 1 1 3-CF₃ H —CH₂NMe₂

118ether491.4 34(l) 1 1 4-CF₃ H —OH

131-132iso ether/DCM— 35(m) 1 1 4-Cl H —OH

190-191iso ether/DCM— 36 1 1 4-Cl H Double bond

139-141iso ether/DCM— 37 1 1 4-Cl H —CH₂NH₂

TFA—429.4 38(n) 1 1 3-CH₃ H —OH

176acetonitrile— 39(o) 1 1 3-CH₃ H Double bond

133iso ether— 40(p) 1 1 3-OCH₃ H —OH

133iso ether/DCM412.4 41(q) 1 1 3-OCH₃ H Double bond

191-192; oxalateMeOH394.3 (base) 42(r) 1 1 3-CF₃ 4-Cl —OH

174-176DCM/isoether/hexane— 43(s) 1 1 3-CF₃ 4-Cl Double bond

128-147,1.5 oxalateMeOH/ether533.3 (base) 44(r) 1 1 3-CF₃ 4-Cl —OH

167-169DCM/iso ether— 45(t) 1 1 3-CF₃ 4-Cl Double bond

160-170; 3 HClether— 46(r) 1 1 3-CF₃ 4-Cl —OH

178-179MeOH/iso ether— 47(u) 1 1 3-CF₃ 4-Cl Double bond

239-241, 2 HClether— 48 1 2 3-CF₃ 4-Cl —OH

124iso ether— 49(v) 1 2 3-CF₃ 4-Cl Double bond

133-164;1.5 oxalateiso ether/MeOH— 50(w) 1 1 3-CF₃ 4-Cl —NHCOMe

209-210; oxalateMeOH/ether— 51(x) 1 1 3-OCF3 H —OH

133iso ether466.4 (base) 52(b) 1 1 3-CF₃ H —OH

201-202;1.5 oxalateMeOH— 53(y) 1 1 3-CF₃ H Double bond

95-108; 1.5 HClether499.4 54(a) 1 1 3-CF₃ H —OH

161iso ether484.3 55(a) 1 1 3-CF₃ H —OH

129iso ether— 56(z) 1 1 3-CF₃ H —CH₂NH₂

3 HClether479.4 57 1 1 3-CF₃ H —CH₂NHMe

137-139iso ether477.4 58 1 1 3-CF₃ H —CH₂NHi-Pr

140-141ether505.3 59 1 1 3-CF₃ H —CH₂N(Me)i-Pr

185-200; 3HClether519.3 60(aa) 1 1 3-CF₃ H —CH₂NHi-Bu

111-112ether519.3 61(ab) 1 1 3-CF₃ H —CH₂N(Me)i-Bu

148-190; 3HClether533.3 62(aa) 1 1 3-CF₃ H —-CH₂NEt₂

98;iso ether/heptane519.3 63(aa) 1 1 3-CF₃ H —CH₂NHi-Pe

137-138:ether533.4 64(ab) 1 1 3-CF₃ H —CH₂N(Me)i-Pe

3 HCl;ether533.3 65 1 1 3-Cl H —CH₂NH₂

138-139DCM/iso ether429.3 66(z) 1 1 3-CF₃ H —CH₂NH₂

204-224; 2 HClether564.3 67(w) 1 1 3-CF₃ 4-Cl —NHCOMe

162-165MeOH/iso ether— 68(w) 1 1 3-CF₃ 4-Cl —NHCOMe

112-134iso ether/hexane— 69 1 1 3-OCH₃ H —CH₂NH₂

120; dioxalateether425.4 70(a) 1 1 3-CF₃ H —OH

HClether463.3 71(a) 1 1 3-CF₃ H —OH

186DCM/iso ether517.3 72(ac) 1 1 3-CF₃ H

176-177iso ether517.6 73(a) 1 1 3-CF₃ H —OH

95-96DCM/iso ether551.2 74(a) 1 1 3-CF₃ H —OH

163DCM/iso ether484.3 75(a) 1 1 3-CF₃ H —OH

171-172DCM/iso ether484.3 765.65(c) 2 1 3-CF₃ H —OH

2HClether565.3 (a) Compound prepared by the procedure described inExample 1, from the compound obtained in preparation 2.2 and thecorresponding compound of formula (III). (b) Compound prepared by theprocedure described in Example 2, from the compound obtained inpreparation 2.2 and the corresponding compound of formula (III). (c)Compound prepared by the procedure described in Example 3, from thecompound obtained in preparation 2.3 and the corresponding compound offormula (III). (d) Compound prepared by the procedure described inExample 1, from the compound obtained in preparation 2.4 and thecorresponding compound of formula (III). (e) Compound prepared by theprocedure described in Example 2, from the compound obtained inpreparation 2.5 and the corresponding compound of formula (III). (f)Compound prepared by the procedure described in Example 1, from thecompound obtained in preparation 2.8 and the corresponding compound offormula (III). (g) Compound prepared by the procedure described inExample 1, from the compound obtained in preparation 2.9 and thecorresponding compound of formula (III). (h) Compound prepared by theprocedure described in Example 6, from Compound No. 11. (i) Compoundprepared by the procedure described in Example 6, from Compound No. 12.(j) Compound prepared by the procedure described in Example 6, fromCompound No. 26. (k) Compound prepared by the procedure described inExample 1, from the compound obtained in preparation 2.11 and thecorresponding compound of formula (III). (l) Compound prepared by theprocedure described in Example 1, from the compound obtained inpreparation 2.12 and the corresponding compound of formula (III). (m)Compound prepared by the procedure described in Example 1, from thecompound obtained in preparation 2.13 and the corresponding compound offormula (III). (n) Compound prepared by the procedure described inExample 1, from the compound obtained in preparation 2.15 and thecorresponding compound of formula (III). (o) Compound prepared by theprocedure described in Example 6, from Compound No. 38. (p) Compoundprepared by the procedure described in Example 1, from the compoundobtained in preparation 2.16 and the corresponding compound of formula(III). (q) Compound prepared by the procedure described in Example 6,from Compound No. 40. (r) Compound prepared by the procedure describedin Example 1, from the compound obtained in preparation 2.17 and thecorresponding compound of formula (III). (s) Compound prepared by theprocedure described in Example 6, from Compound No. 42. (t) Compoundprepared by the procedure described in Example 10, from Compound No. 44.(u) Compound prepared by the procedure described in Example 10, from thecompound from Example 46. (v) Compound prepared by the proceduredescribed in Example 6, from Compound No. 48. (w) Compound prepared bythe procedure described in Example 2, from the compound obtained inpreparation 2.18 and the corresponding compound of formula (III). (x)Compound prepared by the procedure described in Example 1, from thecompound obtained in preparation 2.19 and the corresponding compound offormula (III). (y) Compound prepared by the procedure described inExample 6, from Compound No. 52. (z) Compound prepared by the proceduredescribed in steps A′ and then B′ from Example 4, from the compoundobtained in preparation 2.7 and the corresponding compound of formula(III). (aa) Compound prepared by the procedure described in Example 13,from Compound No. 4 and the corresponding aldehyde. (ab) Compoundprepared by the procedure described in Example 14. (ac) Compoundprepared by the procedure described in Example 1, from the compoundobtained in preparation 2.23 and the corresponding compound of formula(III).

The compounds according to the invention were subjected to biochemicalstudies.

Cell Culture:

The SH-SY-5Y strain (human neuroblastoma) is cultured conventionally ina DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL,France) containing FCS (5%) (foetal calf serum) (Boehringer Mannheim,Germany), sodium pyruvate (1 mM), anti-PPLO (5 ml) (antimycoplasmaagent: Tylocine® prepared in a normal saline solution, 6000 μg/ml),gentamycin (0.1 mg/ml) and glutamine (4 mM) in collagen-coated cultureflasks (Becton Dickinson, France).

The stock strain SK-N-BE (human neuroblastoma) and the clone Bep 75expressing the human p75^(NTR) receptor (SK-N-BE Bep 75) areconventionally cultured in a DMEM culture medium containing FCS (5%),sodium pyruvate (1 mM), anti-PPLO (5 ml), gentamycin (0.1 mg/ml) andglutamine (4 mM).

Study of the Binding of ¹²⁵I-NGF to the p₇₅ ^(NTR) Receptor

The study of the binding of ¹²⁵I-NGF (neuronal growth factorradiolabelled with iodine-125) is carried out on a cellular suspensionof the two strains SH-SY-5Y and SK-N-BE Bep 75 in accordance with themethod described by Weskamp (Neuron, 1991, 6, 649-663). Nonspecificbinding is determined by measuring the total binding after one hour ofpreincubation with the cells at 37° C. in the presence ofnonradiolabelled NGF (1 μM). The specific binding is calculated by thedifference between the measurement of total binding and the measurementof nonspecific binding. The competition experiments are carried outusing a ¹²⁵I-NGF concentration of 0.3 nM. The concentrations inhibitingby 50% (IC₅₀) the binding of ¹²⁵I-NGF to the p75^(NTR) receptor of thecompounds according to the invention are low and vary from 10⁻⁶ to 10⁻¹¹M.

Measurement of Apoptosis:

The cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE Bep 75) areestablished in Petri dishes 35 mm in diameter (Biocoat collagen I) (10⁵cells/well) in a DMEM culture medium containing 5% FCS for 24 h. Theculture medium is then removed, the cells are rinsed with PBS(Dulbecco's phosphate buffered saline) and either fresh mediumcontaining 5% FCS or medium containing NGF at the concentration of 10ng/ml is added in the presence or absence of the compounds according tothe invention. The levels of apoptosis are measured 48 hours after thetreatments in the case of the strain SH-SY-5Y and 24 hours later in thecase of the strain SK-N-BE Bep 75 by quantifying the cytoplasmichistones associated with the DNA fragments (cell death detection ELISA,Boehringer Mannheim, Germany). The levels of apoptosis are expressed asquantity of oligonucleosomes/105 cells±SD. Each value corresponds to themean of 9 experimental points distributed over 3 independentexperiments. The compounds of formula (I) exhibit NGF-induced apoptosisinhibitory activity with IC₅₀ values varying from 10⁻⁶ to 10⁻¹¹ M.

Thus the binding of the compounds according to the invention to thep75^(NTR) receptor results, on the one hand, at the biochemical level,in the inhibition of the dimerization of the receptor induced byneurotrophins, and, on the other hand, at the cellular level, in theinhibition of the proapoptotic effect mediated by the p₇₅ ^(NTR)receptor.

The compounds according to the invention can therefore be used for thepreparation of medicaments, in particular of medicaments intended forthe prevention or treatment of any pathology where the p75^(NTR)receptor is involved.

Thus, in another of its aspects, the invention provides medicamentscomprising a compound of formula (I), or an addition salt thereof with apharmaceutically acceptable acid, or alternatively a solvate or ahydrate of the compound of formula (I).

Thus the compounds according to the invention may be used, in humans orin animals, in the treatment or prevention of variousp75^(NTR)-dependent conditions such as central and peripheralneurodegenerative diseases such as senile dementia, epilepsy,Alzheimer's disease, Parkinson's disease, Huntington's chorea, Down'ssyndrome, prion diseases, amnesia, schizophrenia; amyotrophic lateralsclerosis, multiple sclerosis; cardiovascular conditions such aspost-ischaemic cardiac damage, cardiomyopathies, myocardial infarction,cardiac insufficiency, cardiac ischaemia, cerebral infarction;peripheral neuropathies (of diabetic, traumatic or iatrogenic origin);damage to the optic nerve and to the retina; spinal cord trauma andcranial trauma; atherosclerosis; stenoses; cicatrization; alopecia.

The compounds according to the invention may also be used in thetreatment of cancers such as that of the lung, of the thyroid, of thepancreas, of the prostate, of the small intestine and of the colon, ofthe breast, in the treatment of tumours, of metastases and ofleukaemias.

The compounds according to the invention may also be used in thetreatment of chronic neuropathic and inflammatory pain and in thetreatment of autoimmune diseases such as rheumatoid arthritis.

The compounds according to the invention may also be used in thetreatment of bone fractures and in the treatment or prevention of bonediseases such as osteoporosis.

In another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt, a solvate or a hydrate of the saidcompound, and at least one pharmaceutically acceptable excipient.

The said excipients are selected, according to the pharmaceutical formand the desired mode of administration, from the customary excipientswhich are known to the person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its salt, solvate or hydratewhere appropriate, may be administered in unit form for administration,as a mixture with conventional pharmaceutical excipients, to animals andto human beings for the prophylaxis or treatment of the above disordersor diseases.

The appropriate unit forms for administration comprise the forms fororal administration such as tablets, soft or hard gelatin capsules,powders, granules and oral solutions or suspensions, forms forsublingual, buccal, intratracheal, intraocular or intranasaladministration, forms for administration by inhalation, forms fortopical, transdermal, subcutaneous, intramuscular or intravenousadministration, forms for rectal administration and implants. Fortopical application, the compounds according to the invention may beused in creams, gels, ointments or lotions.

By way of example, a unit form for administration of a compoundaccording to the invention in tablet form may comprise the followingcomponents:

Compound of the invention 50.0 mg Mannitol 223.75 mg Croscaramellosesodium 6.0 mg Cornstarch 15.0 mg Hydroxypropylmethylcellulose 2.25 mgMagnesium stearate 3.0 mg

For oral administration, the dose of active principle administered perday may be up to 0.01 to 100 mg/kg, in single or divided doses,preferably 0.02 to 50 mg/kg.

There may be particular cases in which higher or lower dosages areappropriate; such dosages are not outside the scope of the invention.According to the customary practice, the dosage appropriate for eachpatient is determined by the doctor according to the mode ofadministration, the weight and the response of the said patient.

The present invention, in another of its aspects, also relates to amethod of treating the pathologies indicated above which comprises theadministration, to a patient, of an effective dose of a compoundaccording to the invention, or one of its pharmaceutically acceptablesalts or its hydrates or solvates.

1. A compound of formula (I):

in which: n is 1 or 2; p is 1 or 2; R₁ represents a halogen atom; atrifluoromethyl radical; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; or atrifluoromethoxy radical; R₂ represents a hydrogen atom or a halogenatom; R₃ represents a hydrogen atom; a group —OR₅; a group —CH₂OR₅; agroup —NR₆R₇; a group —NR₈COR₉; a group —NR₈CONR₁₀R₁₁; a group—CH₂NR₁₂R₁₃; a group —CH₂NR₈CONR₁₄R₁₅; a (C₁-C₄)alkoxycarbonyl; or agroup —CONR₁₆R₁₇; or else R₃ constitutes a double bond between thecarbon atom to which it is attached and the adjacent carbon atom of thepiperidine ring; R₄ represents a pyrazinyl  which is being unsubstitutedor being mono- or disubstituted by a substituent selected independentlyfrom a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; and atrifluoromethyl radical; R₅ represents a hydrogen atom; a (C₁-C₄)alkyl;or a (C₁-C₄)alkylcarbonyl; R₆ and R₇ represent each independently ahydrogen atom or a (C₁-C₄)alkyl; R₈ represents a hydrogen atom or a(C₁-C₄)alkyl; R₉ represents a (C₁-C₄)alkyl or a group —(CH₂)_(m)—NR₆R₇;m is 1, 2 or 3; R₁₀ and R₁₁ represent each independently a hydrogen atomor a (C₁-C₄)alkyl; R₁₂ represents a hydrogen atom or a (C₁-C₅)alkyl; R₁₃represents a hydrogen atom, a (C₁-C₅) alkyl, a group —(CH₂)_(q)—OH or agroup —(CH₂)_(q)—S—CH₃; or else R₁₂ and R₁₃, together with the nitrogenatom to which they are attached, constitute a heterocycle selected fromaziridine, azetidine, pyrrolidine, piperidine and morpholine; q is 2 or3; R₁₄ and R₁₅ represent each independently a hydrogen atom or a(C₁-C₄)alkyl; R₁₆ represents a hydrogen atom or a (C₁-C₄)alkyl; R₁₇represents a hydrogen atom, a (C₁-C₅) alkyl, or a group—(CH₂)_(q)—NR₆R₇; or else R₁₆ and R₁₇, together with the nitrogen atomto which they are attached, constitute a heterocycle selected fromazetidine, pyrrolidine, piperidine, morpholine and piperazine which isunsubstituted or substituted in position 4 by a (C₁-C₄)alkyl; or an acidaddition salt thereof.
 2. A compound according to claim 1 wherein: R₁ isin position 2, 3 or 4 of the phenyl and represents a trifluoromethylradical, a chlorine atom, a methyl, a methoxy or a trifluoromethoxyradical and R₂ represents a hydrogen atom; or else R₁ is in position 3of the phenyl and represents a trifluoromethyl radical and R₂ is inposition 4 of the phenyl and represents a chlorine atom.
 3. A compoundaccording to claim 1 wherein: R₃ represents a hydrogen atom, a hydroxyl,a methoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, anacetylamino, an aminomethyl, a (methylamino)methyl, a(dimethylamino)methyl, a (diethylamino)methyl, an(isopentylamino)methyl, an (N-methylisopentylamino)methyl, an(isobutylamino)methyl; an (N-methylisobutylamino)methyl, an(isopentylamino)methyl, an (N-methylisopentylamino)methyl, anaminocarbonyl, or an azetidin-1-ylcarbonyl; or else R₃ constitutes adouble bond between the carbon atom to which it is attached and theadjacent carbon atom of the piperidine ring.
 4. A compound according toclaim 1 wherein: R₄ represents a 2-pyrazinyl, a 5-chloro-2-pyrazinyl, ora 6-chloro-2-pyrazinyl.
 5. A compound according to claim 1 wherein: n is1 or 2; p is 1 or 2; R₁ is in position 2, 3 or 4 of the phenyl andrepresents a trifluoromethyl radical, a chlorine atom, a methyl, amethoxy or a trifluoromethoxy radical and R₂ represents a hydrogen atom;or else R₁ is in position 3 of the phenyl and represents atrifluoromethyl radical and R₂ is in position 4 of the phenyl andrepresents a chlorine atom; R₃ represents a hydrogen atom, a hydroxyl, amethoxy, an (acetyloxy)methyl, a hydroxymethyl, a dimethylamino, anacetylamino, an aminomethyl, a (methylamino)methyl, a(dimethylamino)methyl, a (diethylamino)methyl, an(isopropylamino)methyl, an (N-methylisopropylamino)methyl; an(isobutylamino)methyl; an (N-methylisobutylamino)methyl, an(isopentylamino)methyl, an (N-methylisopentylamino)methyl, anaminocarbonyl, or an azetidin-1-ylcarbonyl; or else R₃ constitutes adouble bond between the carbon atom to which it is attached and theadjacent carbon atom of the piperidine ring; R₄ represents a2-pyrazinyl, a 5-chloro-2-pyrazinyl, or a 6-chloro-2-pyrazinyl.
 6. Acompound according to claim 1 wherein: n is 1; p is 1; R₁ is in position2, 3 or 4 of the phenyl and represents a trifluoromethyl radical, achlorine atom, a methoxy or a trifluoromethoxy radical and R₂ representsa hydrogen atom; or else R₁ is in position 3 of the phenyl andrepresents a trifluoromethyl radical and R₂ is in position 4 of thephenyl and represents a chlorine atom; R₃ represents a hydroxyl, adimethylamino, an aminomethyl, a (methylamino)methyl, a(dimethylamino)methyl, a (diethylamino)methyl, an(isopropylamino)methyl, an (isobutylamino)methyl, an(isopentylamino)methyl, an (N-methylisopentylamino)methyl or anaminocarbonyl; or else R₃ constitutes a double bond between the carbonatom to which it is attached and the adjacent carbon atom of thepiperidine ring; and —R₄ represents a 2-pyrazinyl.
 7. A process forpreparing a compound according to claim 1 in which n=1 wherein acompound of formula (IIA)

 in which R₁, R₂ and R₃ are as defined in claim 1 and Hal represents ahalogen atom, with the proviso that when R₃ contains a hydroxyl or aminefunction these functions may be protected, is reacted with a compound offormula (III)

 in which p and R₄ are as defined in claim 1; and deprotection of thehydroxyl or amine functions present in R₃ where appropriate.
 8. Aprocess for preparing a compound according to claim 1 in which n=2wherein a compound of formula IIb

 in which R₁, R₂ and R₃ are as defined in claim 1, with the proviso thatwhen R₃ contains a hydroxyl or amine function these functions may beprotected, is reacted with a compound of formula (III)

 in which p and R₄ are as defined in claim 1; and deprotection of thehydroxyl or amine functions present in R₃ where appropriate.
 9. Aprocess for preparing a compound according to claim 1 in which R₃represents a group —CH₂NR₁₂R₁₃ in which R₁₂ and R₁₃ each representhydrogen wherein a compound of formula (IIc) or (IId)

 in which R₁ and R₂ are as defined in claim 1 and Hal represents ahalogen atom, is reacted with a compound of formula (III)

 in which p and R₄ are as defined in claim 1 to give a compound offormula (Ia)

 and the cyano group of the compound of formula (Ia) is reduced.
 10. Acompound of formula (Ia)

in which: n is 1 or 2; p is 1 or 2; R₁ represents a halogen atom; atrifluoromethyl radical; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; or atrifluoromethoxy radical; R₂ represents a hydrogen atom or a halogenatom; R₄ represents a pyrazinyl:  which is being unsubstituted or mono-or disubstituted by a substituent selected independently from a halogenatom, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a trifluoromethoxy radical; or anacid addition salt thereof.
 11. A compound according to claim 1 selectedfrom the group consisting of:1-[4-(aminomethyl)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-hydroxy-4-[2-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;2-[4-(2-pyrazinyl)-1-piperazinyl]-1-[4-[2-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-1-ethanone;1-[2-[4-(2-pyrazinyl)-1-piperazinyl]acetyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxamide;1-[4-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(dimethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-(4-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[4-chloro-3-(trifluoromethyl)phenyl]-3,6-dihydro-1(2H)-pyridyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(methylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(diethylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(isopropylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(isobutylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(isopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;1-[4-[(N-methylisopentylamino)methyl]-4-[3-(trifluoromethyl)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;and1-[4-hydroxy-4-[3-(trifluoromethoxy)phenyl]-1-piperidyl]-2-[4-(2-pyrazinyl)-1-piperazinyl]-1-ethanone;or an acid addition salt thereof.
 12. A pharmaceutical compositioncomprising a compound according to claim 1 together with apharmaceutically acceptable excipient.
 13. A pharmaceutical compositioncomprising a compound according to claim 2 together with apharmaceutically acceptable excipient.
 14. A pharmaceutical compositioncomprising a compound according to claim 3 together with apharmaceutically acceptable excipient.
 15. A pharmaceutical compositioncomprising a compound according to claim 4 together with apharmaceutically acceptable excipient.
 16. A pharmaceutical compositioncomprising a compound according to claim 5 together with apharmaceutically acceptable excipient.
 17. A pharmaceutical compositioncomprising a compound according to claim 6 together with apharmaceutically acceptable excipient.
 18. A pharmaceutical compositioncomprising a compound according to claim 11 together with apharmaceutically acceptable excipient.
 19. A method for the treatment ofpain, Parkinson's disease, prostate cancer, and atherosclerosis, whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim
 1. 20.A method for the treatment of pain, Parkinson's disease, prostatecancer, and atherosclerosis, which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 2. 21. A method for the treatment of pain,Parkinson's disease, prostate cancer, and atherosclerosis, whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim
 3. 22.A method for the treatment of pain, Parkinson's disease, prostatecancer, and atherosclerosis, which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 4. 23. A method for the treatment of pain,Parkinson's disease, prostate cancer, and atherosclerosis, whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim
 5. 24.A method for the treatment of pain, Parkinson's disease, prostatecancer, and atherosclerosis, which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 6. 25. A method for the treatment of pain,Parkinson's disease, prostate cancer, and atherosclerosis, whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim 11.